Pyrrole-ring-containing compound, pharmaceutical composition thereof and use thereof

Abstract

Disclosed in the present invention are a pyrrole-ring-containing compound, a pharmaceutical composition thereof and the use thereof. Specifically, disclosed in the present invention are a compound as represented by formula (II), a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof. The compound of the present invention exhibits good agonistic activity against a 5-HT2A receptor.

Description

Pyrrole ring-containing compounds, pharmaceutical compositions thereof and uses thereof

[0001] This application claims priority to the following Chinese patent applications:

[0002] Chinese patent application 2024109732742 with the filing date of July 19, 2024;

[0003] Chinese patent application 2024111531987 with the filing date of August 21, 2024;

[0004] Chinese patent application 2024113819823 with the filing date of September 30, 2024;

[0005] Chinese patent application 2025101194036 with the filing date of January 24, 2025;

[0006] Chinese patent application 2025102357492 with the filing date of February 28, 2025;

[0007] Chinese patent application 202510966139X with the filing date of July 11, 2025.

[0008] This application incorporates the entire text of the above-mentioned Chinese patent applications. TECHNICAL FIELD

[0009] The present application relates to pyrrole ring-containing compounds, pharmaceutical compositions thereof and uses thereof. BACKGROUND

[0010] Currently, drugs targeting the regulation of the serotonin system, such as selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, monoamine oxidase inhibitors, and the like, have been widely used in the treatment of mental disorders such as depression, anxiety, schizophrenia and the like. However, the above-mentioned therapies have slow onset, insufficient drug efficacy or drug resistance for some patients, and side effects such as insomnia, blood pressure and weight changes, resulting in poor patient compliance.

[0011] Changes in synaptic connectivity and plasticity have been observed in the brains of individuals with neurological diseases and disorders. In recent years, preclinical and clinical studies have found that hallucinogens such as ketamine, psilocybin, ibogaine and lysergic acid diethylamide (LSD) have a fast onset, and the long-lasting effects may be due to their unique receptor affinity and regulation of neural plasticity. Therefore, the development of drugs that regulate neural plasticity has broad application prospects for the treatment of neuropsychiatric diseases. SUMMARY

[0012] The technical problem to be solved by the present application is to provide a 5-HT 2A receptor partial agonist. The compound of the present application shows good agonistic activity on 5-HT 2A receptor.

[0013] The present application solves the above technical problem by the following technical scheme.

[0014] The present application provides a compound as shown in formula (II), a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof:

[0015] wherein,

[0016] The configuration of the carbon atom marked with "*" is R configuration, S configuration or a mixture thereof;

[0017] R is C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkynyl or C1-C6 alkyl substituted by one or more R a substituted C1-C6 alkyl;

[0018] R a is D, OH, C3-C6 cycloalkyl, cyano, halogen or -S(=O)2C1-C6 alkyl;

[0019] X1 is N or CH;

[0020] X2 is N or CR 2 ;

[0021] R 2 is H or halogen;

[0022] R 1 is H, hydroxyl, halogen, CN, C1-C6 alkyl, -S(=O)2C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C1-C6 alkyl substituted by one or more R 1-1 substituted C1-C6 alkyl or C1-C6 alkoxy substituted by one or more R 1-2 substituted C1-C6 alkyl;

[0023] R 1-1 and R 1-2 are each independently halogen;

[0024] Alternatively, R 1 and R 2 together with the atom to which they are attached form a 5-6 membered heterocyclene, wherein the heteroatom(s) is / are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0025] X3 is N or CR 3 ;

[0026] R 3 is H or halogen;

[0027] R 3 is H or halogen; 1 together with the atom to which they are attached form a 5-6 membered heterocycloalkenyl, wherein the heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0028] X4is N or CR 4 ;

[0029] R 4 is H or halogen;

[0030] R 5 is H or C1-C6alkyl;

[0031] said compound of formula (I) is not any one of the following compounds:

[0032] In certain preferred embodiments of the application, certain groups in said compound of formula (II), pharmaceutically acceptable salts thereof, solvates thereof or solvates of the pharmaceutically acceptable salts thereof are defined as follows, and the groups not mentioned are as defined in any of the schemes of the application (simply referred to as "in a scheme of the application").

[0033] In a scheme of the application, in said compound of formula (II),

[0034] the configuration of the carbon atom marked with an asterisk is R configuration, S configuration or a mixture thereof;

[0035] R is C1-C6alkyl, C3-C6cycloalkyl, C2-C6alkynyl or C1-C6alkyl substituted with one or more R a ;

[0036] R a is D, OH, C3-C6cycloalkyl, cyano, halogen or -S(=O)2C1-C6alkyl;

[0037] X1is N or CH;

[0038] X2is N or CR 2 ;

[0039] R 2 is H or halogen;

[0040] R 1H, halogen, CN, C1-C6alkyl, -S(=O)2C1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl, substituted C1-C6alkyl by one or more R 1-1 substituted C1-C6alkyl by one or more R 1-2 substituted C1-C6alkyl by one or more R

[0041] R 1-1 and R 1-2 each independently is halogen;

[0042] or, R 1 and R 2 together with the atom to which they are attached form a 5-6 membered heterocyclene, said 5-6 membered heterocyclene having one or more heteroatoms selected from the group consisting of N, O and S, the number of heteroatoms being 1, 2 or 3;

[0043] X3is N or CR 3 ;

[0044] R 3 is H or halogen;

[0045] or, R 3 and R 1 together with the atom to which they are attached form a 5-6 membered heterocyclene, said 5-6 membered heterocyclene having one or more heteroatoms selected from the group consisting of N, O and S, the number of heteroatoms being 1, 2 or 3;

[0046] X4is N or CR 4 ;

[0047] R 4 is H or halogen;

[0048] R 5 is H or C1-C6alkyl;

[0049] said compound of formula (I) is not any one of the following compounds:

[0050] In one embodiment of the present application, said compound of formula (II) is a compound of formula (I) as follows:

[0051] wherein,

[0052] is preferably is

[0053] R is C1-C6alkyl, C3-C6cycloalkyl, C2-C6alkynyl or substituted C1-C6alkyl by one or more R asubstituted C1-C6alkyl;

[0054] R a is D, OH, C3-C6cycloalkyl, cyano, halogen or -S(=O)2C1-C6alkyl;

[0055] X1is N or CH;

[0056] X2is N or CR 2 ;

[0057] R 2 is H or halogen;

[0058] R 1 is H, halogen, CN, C1-C6alkyl, -S(=O)2C1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl, substituted C1-C6alkyl by one or more R 1-1 substituted C1-C6alkyl by one or more R 1-2 substituted C1-C6alkoxy;

[0059] R 1-1 and R 1-2 are each independently halogen;

[0060] or, R 1 and R 2 together with the atom to which they are attached form a 5-6 membered heterocyclene, said 5-6 membered heterocyclene having one or more heteroatoms selected from the group consisting of N, O and S, the number of heteroatoms being 1, 2 or 3;

[0061] X3is N or CR 3 ;

[0062] R 3 is H or halogen;

[0063] or, R 3 and R 1 together with the atom to which they are attached form a 5-6 membered heterocyclene, said 5-6 membered heterocyclene having one or more heteroatoms selected from the group consisting of N, O and S, the number of heteroatoms being 1, 2 or 3;

[0064] X4is N or CR 4 ;

[0065] R 4 is H or halogen;

[0066] said compound of formula (I) is not any one of the following compounds:

[0067] In one embodiment of the present application, the compound of formula (I) or the compound of formula (II) is also not any one of the following compounds:

[0068] In a certain embodiment of the application, each "halogen" is, independently from each other, F, Cl, Br or I, for example F.

[0069] In a certain embodiment of the application, each "Ci-C6-alkoxy" is, independently from each other, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy or t-butoxy, for example methoxy, ethoxy or i-propoxy.

[0070] In a certain embodiment of the application, each "Ci-C6-alkyl" is, independently from each other, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl or t-butyl, for example methyl, ethyl, i-propyl or i-butyl.

[0071] In a certain embodiment of the application, each "C2-C6-alkynyl" is, independently from each other, ethynyl, propynyl or propargyl, for example ethynyl.

[0072] In a certain embodiment of the application, each "C3-C6-cycloalkyl" is, independently from each other, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl.

[0073] In a certain embodiment of the application, each "5-6 membered heterocyclene" is, independently from each other, a 5-6 membered heterocyclene with one or two heteroatoms being O, for example a dihydrofuran or dihydropyran ring, further for example

[0074] In a certain embodiment of the application, is is preferably

[0075] In a certain embodiment of the application, R is -CH3, -CD3, -CH2CH3, for example -CH3or

[0076] In a certain embodiment of the application, R is -CH3, -CD3, -CH2CH3, for example -CH3.

[0077] In a certain embodiment of the application, R is Ci-C6-alkyl.

[0078] In a certain embodiment of the application, R 2 is H or F, or, R 1 and R 2together with the atom to which they are attached form

[0079] In one embodiment of the application, R 2 is H.

[0080] In one embodiment of the application, R 1 is -H, -F, -CN, -CH3, -CF3, -OCH3, or R 1 and R 2 together with the atom to which they are attached form

[0081] In one embodiment of the application, R 1 is -H, -F, -CN, -CH3, -CF3, -OCH3,

[0082] In one embodiment of the application, R 1 and R 2 together with the atom to which they are attached form

[0083] In one embodiment of the application, R 1 is C1-C6alkoxy or halogen, for example methoxy or F.

[0084] In one embodiment of the application, R 1 is C1-C6alkoxy, for example methoxy.

[0085] In one embodiment of the application, R 3 is H or F, for example H.

[0086] In one embodiment of the application, R 4 is H or F, for example H.

[0087] In one embodiment of the application, R 5 is -H or -CH3.

[0088] In one embodiment of the application, R 5 is -H.

[0089] In one embodiment of the application, R 5 is C1-C6alkyl, for example methyl.

[0090] In one embodiment of the application, is

[0091] In an embodiment of the present application, In an embodiment of the present application,

[0092] In an embodiment of the present application, In an embodiment of the present application,

[0093] In an embodiment of the present application, In an embodiment of the present application,

[0094] In an embodiment of the present application, In an embodiment of the present application,

[0095] In an embodiment of the present application, In an embodiment of the present application,

[0096] In an embodiment of the present application, In an embodiment of the present application,

[0097] In an embodiment of the present application, X2is CR 2 , R 1 and R 2 together with the atom to which they are attached form a 5-6 membered heterocyclen.

[0098] In an embodiment of the present application, the compound of formula (I) is

[0099] In an embodiment of the present application,

[0100] R is C1-C6alkyl or C1-C6alkyl substituted with one or more hydroxyl groups, for example C1-C6alkyl;

[0101] R 1 is halogen or C1-C6alkoxy;

[0102] R 2 , R 3 and R 4 are each independently H or halogen.

[0103] In an embodiment of the present application, the compound of formula (I) is

[0104] In an embodiment of the present application,

[0105] R 1 is halogen or C1-C6alkoxy;

[0106] R is C1-C6alkyl.

[0107] In an embodiment of the present application, the compound of formula (I) is a compound selected from the group consisting of:

[0108]

[0109] R 1 R 2 R and the atom to which they are attached together form a 5-6 membered heterocycloalkenyl, wherein the heteroatom is O, and the number of heteroatoms is 1;

[0110] R is C1-C6 alkyl or C1-C6 alkyl substituted with one or more hydroxyl groups.

[0111] In an embodiment of the present application, the compound of formula (I) is a compound selected from the group consisting of:

[0112]

[0113] R 1 R is C1-C6 alkyl or C1-C6 alkyl substituted with one or more hydroxyl groups.

[0114] R is C1-C6 alkyl or C1-C6 alkyl substituted with one or more hydroxyl groups.

[0115] In an embodiment of the present application, the compound of formula (II) is a compound selected from the group consisting of:

[0116] The present application also provides a pharmaceutical composition comprising a compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, according to any one of the above embodiments, and a pharmaceutically acceptable excipient.

[0117] The present application also provides a use of a compound, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition in the manufacture of a medicament for modulating neuronal plasticity.

[0118] The present application also provides a use of a compound, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition in the manufacture of a medicament for preventing and / or treating depression, schizophrenia, anxiety, or post-traumatic stress disorder.

[0119] The present application also provides a use of a compound, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition in the manufacture of a medicament for 5-HT 2A ​​application; preferably, the 5-HT 2A application is a 5-HT 2A application is a 5-HT 2B application is a 5-HT 2A application is a 5-HT

[0120] The present application also provides use of a compound, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described in any of the above aspects in the preparation of a medicament for preventing and / or treating a disease related to 5-HT 2A application; preferably, the disease related to 5-HT 2A application is depression, schizophrenia, anxiety or post-traumatic stress disorder.

[0121] In addition to the foregoing, the following terms shall have the meanings indicated below when used in the specification and claims herein, unless otherwise indicated specifically and explicitly:

[0122] The term "pharmaceutically acceptable salt" refers to those salts of the compounds of the present application which are relatively non-toxic, pharmaceutically acceptable salts prepared from a relatively nontoxic, pharmaceutically acceptable acid or base. When a compound of the present application contains relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired pharmaceutically acceptable base, either neat or in a suitable inert solvent. When a compound of the present application contains relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired pharmaceutically acceptable acid, either neat or in a suitable inert solvent.

[0123] The term "solvate" refers to a compound in combination with a solvent. Solvates are classified into stoichiometric solvates and non-stoichiometric solvates.

[0124] The term "solvate of a pharmaceutically acceptable salt" refers to a compound in combination with a pharmaceutically acceptable acid or base, a solvent. The amount of solvent can be stoichiometric or non-stoichiometric.

[0125] The term "halogen" refers to F, Cl, Br, I.

[0126] The term "alkyl" refers to a straight or branched chain, saturated, monovalent hydrocarbon group having the indicated number of carbon atoms (e.g., C 1-6 ) atoms. Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, and the like.

[0127] The term "alkoxy" refers to the group -O-R X , wherein RX alkyl as defined above.

[0128] The term "alkynyl" refers to a straight-chain or branched hydrocarbon group having one or more triple bonds of a specified number of carbon atoms (e.g., C2-C6alkynyl). The one or more carbon-carbon triple bonds can be internal or terminal.

[0129] The term "cycloalkyl" refers to a saturated cyclic group having a specified number of ring carbon atoms (e.g., C3-C6), the ring atoms consisting solely of carbon atoms.

[0130] The term "heterocycloalkenyl" refers to an unsaturated cyclic group having a specified number of ring atoms (e.g., 5-6 membered), a specified number of heteroatoms (e.g., 1, 2, or 3), a specified type of heteroatoms (one or more of N, O, and S), and no aromaticity.

[0131] As understood by one skilled in the art, the use of in the structural formula of a group described herein refers to the corresponding group R being connected to other fragments, groups in the compound through the site.

[0132] The term "one or more" refers to 1, 2, 3, 4, or more.

[0133] The term "pharmaceutically acceptable excipients" refers to excipients and additives used in the production and formulation of pharmaceutical products, and are all substances contained in pharmaceutical preparations other than active ingredients. Please refer to the Pharmacopoeia of the People's Republic of China (2020 Edition) Volume IV, or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition).

[0134] On the basis of common sense in the art, the above-mentioned preferred conditions can be combined arbitrarily, i.e., to obtain each preferred example of the present application.

[0135] The reagents and raw materials used in the present application are commercially available.

[0136] The positive progress effect of the present application is that the compound of the present application has one or more of the following advantages:

[0137] (1) The compound of the present application shows good agonistic activity on 5-HT 2A receptors;

[0138] (2) The compound of the present application has good selective agonistic activity on 5-HT 2B receptors relative to 5-HT 2A receptors;

[0139] (3) The compound of the present application can promote the growth of primary rat cortical neuron cells, and has the ability to regulate the dendritic nerve plasticity of neurons;

[0140] (4) The compound of the present application has the properties of low liver microsomal clearance rate and good metabolic stability;

[0141] (5) The compound of the present application has a small risk of inhibiting hERG potassium ion channel, IC 50 even up to 10 μM or more;

[0142] (6) The compound of the present application has good pharmacokinetic properties;

[0143] (7) The compound of the present application has no hallucinogenicity;

[0144] (8) The compound of the present application has no effect on the spontaneous activity of the subject;

[0145] (9) The compound of the present application has excellent antidepressant efficacy. DETAILED DESCRIPTION

[0146] The present application will be further described by way of examples below, but the present application is not limited in the scope of the examples. The experimental methods in the following examples without specific conditions are selected according to the conventional methods and conditions, or according to the instructions of the commercial products.

[0147] Example 1

[0148] Synthetic route:

[0149] First step

[0150] Dissolve (R)-N-carboxylic acid tert-butyl ester-azetidine-2-carboxylic acid (4.40 g, 21.8 mmol) in dichloromethane (50 mL), drop in oxalyl chloride (2.24 mL, 26.2 mmol) at 0 °C, stir the reaction solution at 0 °C for 10 min, slowly add N,N-dimethylformamide (160 mg, 2.32 mmol), stir the reaction solution at 25 °C for 1 h. Concentrate the reaction solution under reduced pressure to obtain the crude intermediate. Dissolve compound 1-1 (2.00 g, 13.1 mmol) in dichloromethane (20 mL), slowly drop in ethyl magnesium bromide (6.86 mL, 14.4 mmol, 2 mol / L) under nitrogen atmosphere at 0 °C, stir at 0 °C for 0.5 h. Dissolve the crude intermediate in dichloromethane (30 mL), drop into the reaction solution at 0 °C, stir the reaction solution at 0 °C for 0.5 h. Add saturated aqueous citric acid solution (100 mL) to the reaction solution, extract with dichloromethane (60 mL x 3), combine the organic phases, wash with saturated brine (100 mL x 2). Dry the organic phase over anhydrous sodium sulfate, filter, concentrate under reduced pressure, purify the crude product by silica gel column chromatography (dichloromethane / ethyl acetate, 1 / 1, v / v) to obtain compound 1-2. ESI-MS Theoretical value: [M+H-56] = 281.13, Found 281.0. +

[0151] Second step

[0152] Dissolve compound 1-2 (250 mg, 0.74 mmol) in tetrahydrofuran (20 mL), drop in tetrahydrofuran solution of lithium aluminum hydride (2.96 mL, 7.40 mmol, 2.5 mol / L) at 0 °C, stir the reaction solution at 60 °C for 12 h under nitrogen atmosphere. Cool the reaction solution to room temperature, quench with ice water (0.29 mL), add 15% aqueous sodium hydroxide solution (0.29 mL) and water (0.87 mL), filter, concentrate the filtrate under reduced pressure to obtain the crude product of the target compound, purify by high performance liquid chromatography (Waters-XBndge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L aqueous ammonium bicarbonate solution, gradient: 25-30%, retention time: 10.95-13.35 min, run time: 18 min) to obtain compound 1. 1 ​H NMR (400 MHz, DMSO-d6): δ 10.95 (s, 1H), 7.49 (dd, J = 11.6, 7.6 Hz, 1H), 7.30 (dd, J = 11.6, 7.6 Hz, 1H), 7.17 (d, J = 1.6 Hz, 1H), 3.24-3.19 (m, 1H), 3.12-3.04 (m, 1H), 2.88-2.83 (m, 1H), 2.74-2.68 (m, 1H), 2.62-2.56 (m, 1H), 2.09 (s, 3H), 1.94-1.87 (m, 1H), 1.80-1.71 (m, 1H). ESI-MS Theoretical calculation value: [M+H] + = 237.11, found 237.0.

[0153] Example 2

[0154] Synthetic route:

[0155] First step

[0156] (R)-N-carboxylic acid tert-butyl ester-azetidine-2-carboxylic acid (2.20 g, 10.9 mmol) was dissolved in dichloromethane (25 mL), oxalyl chloride (1.12 mL, 13.1 mmol) was added dropwise at 0 °C, the reaction solution was stirred at 0 °C for 10 min, N,N-dimethylformamide (80.0 mg, 1.16 mmol) was slowly added, the reaction solution was stirred at 25 °C for 1 h. The reaction solution was concentrated under reduced pressure to obtain the crude intermediate. Compound 2-1 (1.00 g, 6.05 mmol) was dissolved in dichloromethane (10 mL), ethyl magnesium bromide (3.18 mL, 6.35 mmol, 2 mol / L) was slowly added dropwise under nitrogen atmosphere at 0 °C, and the reaction solution was stirred at 0 °C for 0.5 h. The crude intermediate was dissolved in dichloromethane (15 mL), which was added dropwise to the reaction solution at 0 °C, and the reaction solution was stirred at 0 °C for 0.5 h. The reaction solution was added to saturated aqueous citric acid solution (50 mL), extracted with dichloromethane (30 mL x 3), and the organic phase was combined and washed with saturated brine (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / ethyl acetate, 1 / 1, v / v) to obtain compound 2-2. ESI-MS Theoretical calculation value: [M+H-56] + = 293.15, found 293.1.

[0157] Second step

[0158] Compound 2-2 (94.0 mg, 0.27 mmol) was dissolved in tetrahydrofuran (9 mL), tetrahydro-lithium aluminum solution in tetrahydrofuran (1.08 mL, 2.70 mmol, 2.5 mol / L) was added dropwise at 0 °C, the reaction solution was stirred at 60 °C for 12 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, ice water (0.1 mL) was added to quench, 15% sodium hydroxide aqueous solution (0.1 mL) and water (0.3 mL) were added, filtered, the filtrate was concentrated under reduced pressure to obtain the crude product of the target compound, which was purified by high performance liquid chromatography (Waters-XBndge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 19-26%, retention time: 9.80-11.80 min, running time: 17 min) to obtain compound 2. 1 H NMR (400 MHz, DMSO-d6): δ 10.67 (s, 1H), 7.17 (d, J = 8.4 Hz, 1H), 7.13 (d, J = 11.6 Hz, 1H), 7.04 (d, J = 1.8 Hz, 1H), 3.83 (s, 3H), 3.26-3.19 (m, 1H), 3.13-3.05 (m, 1H), 2.89-2.84 (m, 1H), 2.75-2.69 (m, 1H), 2.63-2.59 (m, 1H), 2.11 (s, 3H), 1.97-1.91 (m, 1H), 1.83-1.75 (m, 1H). ESI-MS Theoretical calculation value: [M+H] + = 249.13, found 249.1.

[0159] Example 3

[0160] Synthetic route:

[0161] First step

[0162] Dissolve (R)-N-carboxylic acid tert-butyl ester-azetidine-2-carboxylic acid (4.40 g, 21.8 mmol) in dichloromethane (50 mL), drop in oxalyl chloride (2.24 mL, 26.2 mmol) at 0 °C, stir the reaction solution at 0 °C for 10 min, slowly add N,N-dimethylformamide (160 mg, 2.32 mmol), stir the reaction solution at 25 °C for 1 h. Concentrate the reaction solution under reduced pressure to obtain the crude intermediate. Dissolve compound 3-1 (2.00 g, 14.8 mmol) in dichloromethane (15 mL), slowly drop in ethyl magnesium bromide (7.77 mL, 6.45 mmol, 2 mol / L) under nitrogen atmosphere at 0 °C, stir at 0 °C for 0.5 h. Dissolve the crude intermediate in dichloromethane (10 mL), drop into the reaction solution at 0 °C, stir the reaction solution at 0 °C for 0.5 h. Add saturated aqueous citric acid solution (50 mL) to the reaction solution, extract with dichloromethane (50 mL x 3), combine the organic phases, wash with saturated brine (50 mL x 2). Dry the organic phase over anhydrous sodium sulfate, filter, concentrate under reduced pressure, purify the crude product by silica gel column chromatography (dichloromethane / ethyl acetate, 1 / 1, v / v) to obtain compound 3-2. ESI-MS Theoretical value: [M+H] = 319.14, Found 319.0. +

[0163] Second step

[0164] Dissolve compound 3-2 (100 mg, 0.31 mmol) in tetrahydrofuran (15 mL), drop in tetrahydroaluminum lithium solution in tetrahydrofuran (1.24 mL, 3.10 mmol, 2.5 mol / L) at 0 °C, stir the reaction solution at 60 °C for 12 h under nitrogen atmosphere. Cool the reaction solution to room temperature, quench with ice water (0.1 mL), add 15% aqueous sodium hydroxide solution (0.1 mL) and water (0.3 mL), filter, concentrate the filtrate under reduced pressure to obtain the crude product of the target compound, purify by high performance liquid chromatography (Waters-XBndge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L aqueous ammonium bicarbonate solution, gradient: 21-31%, retention time: 9.20-11.40 min, run time: 17 min) to obtain compound 3. 1 ​H NMR (400 MHz, DMSO-d6): δ 10.87 (s, 1H), 7.30 (dd, J = 8.8, 4.4 Hz, 1H), 7.25 (dd, J = 9.8, 2.4 Hz, 1H), 7.17 (d, J = 2.0 Hz, 1H), 6.90-6.85 (m, 1H), 3.23-3.19 (m, 1H), 3.10-3.05 (m, 1H), 2.87-2.83 (m, 1H), 2.76-2.69 (m, 1H), 2.67-2.59 (m, 1H), 2.09 (s, 3H), 1.94-1.87 (m, 1H), 1.80-1.74 (m, 1H). ESI-MS Theoretical calculation value: [M+H] = 219.12, found 219.1. + = 219.12, found 219.1.

[0165] Example 4

[0166] Synthetic route:

[0167] First step

[0168] (R)-N-carboxylic acid tert-butyl ester-azetidine-2-carboxylic acid (1.47 g, 7.27 mmol) was dissolved in dichloromethane (20 mL), oxalyl chloride (0.75 mL, 8.73 mmol) was added dropwise at 0 °C, the reaction solution was stirred at 0 °C for 10 min, N,N-dimethylformamide (53.3 mg, 0.77 mmol) was slowly added, the reaction solution was stirred at 25 °C for 1 h. The reaction solution was concentrated under reduced pressure to obtain the crude intermediate. Compound 4-1 (1.00 g, 6.05 mmol) was dissolved in dichloromethane (10 mL), ethyl magnesium bromide (3.18 mL, 6.35 mmol, 2 mol / L) was slowly added dropwise under nitrogen atmosphere at 0 °C, and the reaction solution was stirred at 0 °C for 0.5 h. The crude intermediate was dissolved in dichloromethane (15 mL), which was added dropwise to the reaction solution at 0 °C, and the reaction solution was stirred at 0 °C for 0.5 h. The reaction solution was added to saturated aqueous citric acid solution (50 mL), extracted with dichloromethane (50 mL x 3), and the organic phase was combined and washed with saturated brine (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / ethyl acetate, 1 / 1, v / v) to obtain compound 4-2. ESI-MS Theoretical calculation value: [M+H] = 349.15, found 349.0. + = 349.15, found 349.0.

[0169] Second step

[0170] Compound 4-2 (350 mg, 1.00 mmol) was dissolved in tetrahydrofuran (10 mL), tetrahydro-lithium aluminum solution in tetrahydrofuran (4.00 mL, 10.0 mmol, 2.5 mol / L) was added dropwise at 0 °C, the reaction solution was stirred at 60 °C for 12 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, ice water (0.35 mL) was added to quench, 15% sodium hydroxide aqueous solution (0.35 mL) and water (1.05 mL) were added, filtered, the filtrate was concentrated under reduced pressure to obtain the crude product of the target compound, which was purified by high performance liquid chromatography (Waters-XBndge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 20-25%, retention time: 11.25-14.50 min, running time: 19 min) to obtain compound 4. 1 H NMR (400 MHz, DMSO-d6): δ 11.09 (s, 1H), 7.12 (d, J = 2.0 Hz, 1H), 6.85 (d, J = 1.6 Hz, 1H), 6.59 (dd, J = 12.8, 2.0 Hz, 1H), 3.77 (s, 3H), 3.24-3.21 (m, 1H), 3.14-3.07 (m, 1H), 2.89-2.84 (m, 1H), 2.73-2.69 (m, 1H), 2.64-2.57 (m, 1H), 2.11 (s, 3H), 1.96-1.91 (m, 1H), 1.84-1.75 (m, 1H). ESI-MS Theoretical calculation value: [M+H] + = 249.13, found 249.0.

[0171] Example 5

[0172] Synthetic route:

[0173] First step

[0174] Dissolve (R)-N-carboxylic acid tert-butyl ester-azetidine-2-carboxylic acid (1.47 g, 7.27 mmol) in dichloromethane (20 mL), drop in oxalyl chloride (0.75 mL, 8.73 mmol) at 0 °C, stir the reaction solution at 0 °C for 10 min, slowly add N,N-dimethylformamide (53.3 mg, 0.77 mmol), stir the reaction solution at 25 °C for 1 h. Concentrate the reaction solution under reduced pressure to obtain the crude intermediate. Dissolve compound 5-1 (1.10 g, 6.05 mmol) in dichloromethane (15 mL), slowly drop in ethyl magnesium bromide (2.87 mL, 5.74 mmol, 2 mol / L) under nitrogen atmosphere at 0 °C, stir the reaction solution at 0 °C for 0.5 h. Dissolve the crude intermediate in dichloromethane (15 mL), drop into the reaction solution at 0 °C, stir the reaction solution at 0 °C for 0.5 h. Add saturated aqueous citric acid solution (50 mL) to the reaction solution, extract with dichloromethane (50 mL x 3), combine the organic phases, wash with saturated brine (50 mL x 2). Dry the organic phase over anhydrous sodium sulfate, filter, concentrate under reduced pressure, purify the crude product by silica gel column chromatography (dichloromethane / ethyl acetate, 1 / 1, v / v) to obtain compound 5-2. ESI-MS Theoretical value: [M+H] = 385.36, Found 385.0. +

[0175] Second step

[0176] Dissolve compound 5-2 (170 mg, 0.44 mmol) in tetrahydrofuran (10 mL), drop in tetrahydroaluminum lithium solution in tetrahydrofuran (1.76 mL, 4.40 mmol, 2.5 mol / L) at 0 °C, stir the reaction solution at 60 °C for 12 h under nitrogen atmosphere. Cool the reaction solution to room temperature, quench with ice water (0.17 mL), add 15% aqueous sodium hydroxide solution (0.17 mL) and water (0.51 mL), filter, concentrate the filtrate under reduced pressure to obtain the crude product of the target compound, purify by high performance liquid chromatography (Waters-XBndge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-0.1% formic acid aqueous solution, gradient: 18-28%, retention time: 6.2-7.8 min, run time: 17 min) to obtain monomethylate of compound 5. 1 ​H NMR (400 MHz, DMSO-d6): δ 11.14 (s, 1H), 8.26 (s, 1H), 7.52 (s, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.29 (s, 1H), 7.03 (d, J = 8.0 Hz, 1H), 3.43-3.40 (m, 2H), 3.01-2.98 (m, 1H), 2.93-2.84 (m, 2H), 2.21 (s, 3H), 2.07-2.00 (m, 1H), 1.93-1.85 (m, 1H). ESI-MS Theoretical calculation: [M+H] + = 285.28, found 285.0.

[0177] Examples 6 and 7

[0178] Synthetic route:

[0179] First step

[0180] (R)-N-carboxylic acid tert-butyl ester-azetidine-2-carboxylic acid (1.69 g, 8.36 mmol) was dissolved in dichloromethane (20 mL), oxalyl chloride (0.86 mL, 10.0 mmol) was added dropwise at 0 °C, the reaction solution was stirred at 0 °C for 10 min, N,N-dimethylformamide (61.3 mg, 0.89 mmol) was added slowly, the reaction solution was stirred at 25 °C for 1 h. The reaction solution was concentrated under reduced pressure to obtain the crude intermediate. Compound 6-1 (1.30 g, 7.02 mmol) was dissolved in dichloromethane (20 mL), ethyl magnesium bromide (3.86 mL, 7.72 mmol, 2 mol / L) was added dropwise slowly at 0 °C under nitrogen atmosphere, the reaction solution was stirred at 0 °C for 0.5 h. The crude intermediate was dissolved in dichloromethane (20 mL), added dropwise to the reaction solution at 0 °C, the reaction solution was stirred at 0 °C for 0.5 h. The reaction solution was added to saturated aqueous citric acid solution (50 mL), extracted with dichloromethane (50 mL x 3), the combined organic phase was washed with saturated brine (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, the crude product was purified by silica gel column chromatography (dichloromethane / ethyl acetate, 1 / 1, v / v) to obtain compound 6-2. ESI-MS Theoretical calculation: [M+H] + = 369.13, found 368.9.

[0181] Second step

[0182] Compound 6-2 (120 mg, 0.33 mmol) was dissolved in tetrahydrofuran (10 mL), tetrahydroaluminum lithium solution in tetrahydrofuran (1.32 mL, 3.30 mmol, 2.5 mol / L) was added dropwise at 0 °C, the reaction solution was stirred at 60 °C for 16 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, quenched by adding ice water (0.10 mL), 15% sodium hydroxide aqueous solution (0.20 mL) and water (0.10 mL) were added, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of the target compound, which was purified by high performance liquid chromatography (Waters-Agilent-C18-10 μm-19*250 mm, mobile phase: acetonitrile-0.1% formic acid aqueous solution, gradient: 20-30%, run time: 17 min) to obtain a formate salt of compound 6 (retention time: 7.0-8.5 min). 1 H NMR (400 MHz, DMSO-d6): δ 11.31 (s, 1H), 8.25 (s, 1H), 7.92 (s, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.34 (d, J = 9.6 Hz, 2H), 3.34-3.29 (m, 2H), 3.07-2.99 (m, 1H), 2.90-2.84 (m, 1H), 2.80-2.74 (m, 1H), 2.15 (s, 3H), 1.99-1.95 (m, 1H), 1.88-1.80 (m, 1H). ESI-MS Theoretical calculation value: [M+H] + = 269.12, found 269.1. And a formate salt of compound 7 (retention time: 4.0-5.0 min). 1 H NMR (400 MHz, DMSO-d6): δ 10.61 (s, 1H), 8.23 (s, 1H), 7.28 (s, 1H), 7.19 (d, J = 8.4 Hz, 1H), 7.03 (d, J = 2.0 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 3.20-3.17 (m, 1H), 3.12-3.04 (m, 1H), 2.90-2.85 (m, 1H), 2.73-2.65 (m, 1H), 2.62-2.57 (m, 1H), 2.37 (s, 3H), 2.11 (s, 3H), 1.93-1.88 (m, 1H), 1.80-1.73 (m, 1H). ESI-MS Theoretical calculation value: [M+H] + = 215.15, found 215.0.

[0183] Example 8

[0184] Synthetic route:

[0185] First step

[0186] (R)-N-carboxylic acid tert-butyl ester-azetidine-2-carboxylic acid (4.41 g, 21.8 mmol) was dissolved in dichloromethane (50 mL), oxalyl chloride (2.25 mL, 26.2 mmol) was added dropwise at 0 °C, the reaction solution was stirred at 0 °C for 10 min, N,N-dimethylformamide (160 mg, 2.31 mmol) was added slowly, the reaction solution was stirred at 25 °C for 1 h. The reaction solution was concentrated under reduced pressure to obtain the crude intermediate. Compound 8-1 (3.00 g, 20.3 mmol) was dissolved in dichloromethane (30 mL), ethyl magnesium bromide (10.6 mL, 21.3 mmol, 2 mol / L) was added dropwise slowly at 0 °C under nitrogen atmosphere, the reaction solution was stirred at 0 °C for 0.5 h. The crude intermediate was dissolved in dichloromethane (30 mL), added dropwise to the reaction solution at 0 °C, the reaction solution was stirred at 0 °C for 0.5 h. The reaction solution was added to saturated aqueous citric acid solution (50 mL), extracted with dichloromethane (50 mL x 3), the combined organic phase was washed with saturated brine (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, the crude product was purified by silica gel column chromatography (dichloromethane / ethyl acetate, 1 / 1, v / v) to obtain compound 8-2. ESI-MS Theoretical value: [M+H] = 332.15, Found 332.0. +

[0187] Second step

[0188] Compound 8-2 (120 mg, 0.36 mmol) was dissolved in tetrahydrofuran (5 mL), tetrahydroaluminum lithium solution in tetrahydrofuran (1.44 mL, 3.60 mmol, 2.5 mol / L) was added dropwise at 0 °C, the reaction solution was stirred at 60 °C for 16 h under nitrogen atmosphere. The reaction solution was cooled to room temperature, quenched by adding ice water (0.15 mL), 15% sodium hydroxide aqueous solution (0.15 mL) and water (0.45 mL) were added, filtered, the filtrate was concentrated under reduced pressure to obtain the crude product of the target compound, which was purified by high performance liquid chromatography (Waters-Agilent-C18-10 μm-19*250 mm, mobile phase: acetonitrile-0.1% formic acid aqueous solution, gradient: 6-16%, retention time: 6.8-7.8 min, running time: 17 min) to obtain the monohydrochloride salt of compound 8. 1 ​H NMR (400 MHz, DMSO-d6): δ 11.18 (s, 1H), 8.26 (s, 1H), 7.93 (d, J = 2.8 Hz, 1H), 7.52 (d, J = 2.8 Hz, 1H), 7.20 (d, J = 2.0 Hz, 1H), 3.82 (s, 3H), 3.29-3.25 (m, 1H), 3.24-3.20 (m, 1H), 2.93-2.85 (m, 1H), 2.82-2.75 (m, 1H), 2.73-2.69 (m, 1H), 2.14 (s, 3H), 1.99-1.93 (m, 1H), 1.87-1.78 (m, 1H). ESI-MS Theoretical calculation value: [M+H] + = 232.14, found 232.0.

[0189] Example 9

[0190] Synthetic route:

[0191] First step

[0192] (R)-N-carboxylic acid tert-butyl ester-azetidine-2-carboxylic acid (5.29 g, 26.2 mmol) was dissolved in dichloromethane (50 mL), oxalyl chloride (2.70 mL, 31.4 mmol) was added dropwise at 0 °C, the reaction solution was stirred at 0 °C for 10 min, N,N-dimethylformamide (192 mg, 2.77 mmol) was slowly added, the reaction solution was stirred at 25 °C for 1 h. The reaction solution was concentrated under reduced pressure to obtain the crude intermediate. Compound 9-1 (3.00 g, 22.0 mmol) was dissolved in dichloromethane (30 mL), ethyl magnesium bromide (11.6 mL, 23.1 mmol, 2 mol / L) was slowly added dropwise under nitrogen atmosphere at 0 °C, and the reaction solution was stirred at 0 °C for 0.5 h. The crude intermediate was dissolved in dichloromethane (30 mL), and was added dropwise to the reaction solution at 0 °C, and the reaction solution was stirred at 0 °C for 0.5 h. The reaction solution was added to saturated aqueous citric acid solution (50 mL), extracted with dichloromethane (50 mL x 3), and the organic phase was combined and washed with saturated brine (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / ethyl acetate, 1 / 1, v / v) to obtain compound 9-2. ESI-MS Theoretical calculation value: [M+H] + = 320.13, found 320.0.

[0193] Second step

[0194] Compound 9-2 (105 mg, 0.33 mmol) was dissolved in tetrahydrofuran (5 mL), tetrahydroaluminum lithium solution in tetrahydrofuran (1.72 mL, 4.29 mmol, 2.5 mol / L) was added dropwise at 0 °C, the reaction solution was stirred at 60 °C for 16 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, quenched by adding ice water (0.17 mL), 15% sodium hydroxide aqueous solution (0.17 mL) and water (0.51 mL) were added, filtered, the filtrate was concentrated under reduced pressure to obtain the crude product of the target compound, which was purified by high performance liquid chromatography (Waters-Agilent-C18-10 μm-19*250 mm, mobile phase: acetonitrile-0.04% ammonia water solution+7.5 mmol / L of ammonium bicarbonate solution, gradient: 20-30%, retention time: 9.0-10.0 min, running time: 17 min) to obtain compound 9. 1 H NMR (400 MHz, DMSO-d6): δ 11.49 (s, 1H), 8.14 (s, 1H), 7.83 (dd, J = 9.6, 2.4 Hz, 1H), 7.33 (s, 1H), 3.24-3.18 (m, 1H), 3.11-3.06 (m, 1H), 2.90-2.83 (m, 1H), 2.78-2.71 (m, 1H), 2.62-2.56 (m, 1H), 2.08 (s, 3H), 1.92-1.85 (m, 1H), 1.81-1.74 (m, 1H). ESI-MS Theoretical calculation value: [M+H] + = 220.12, found 220.1.

[0195] Example 10

[0196] Synthetic route:

[0197] First step

[0198] Dissolve (R)-N-carboxylic acid tert-butyl ester-azetidine-2-carboxylic acid (1.32 g, 6.55 mmol) in dichloromethane (20 mL), drop in oxalyl chloride (0.675 mL, 7.85 mmol) at 0 °C, stir the reaction solution at 0 °C for 10 min, slowly add N,N-dimethylformamide (48.0 mg, 0.693 mmol), stir the reaction solution at 25 °C for 1 h. Concentrate the reaction solution under reduced pressure to obtain the crude intermediate. Dissolve compound 10-1 (1.00 g, 6.05 mmol) in dichloromethane (20 mL), slowly drop in ethyl magnesium bromide (3.18 mL, 6.35 mmol, 2 mol / L) under nitrogen atmosphere at 0 °C, stir the reaction solution at 0 °C for 0.5 h. Dissolve the crude intermediate in dichloromethane (30 mL), drop into the reaction solution at 0 °C, stir the reaction solution at 0 °C for 0.5 h. Add saturated aqueous citric acid solution (30 mL) to the reaction solution, extract with dichloromethane (30 mL x 3), wash the combined organic phase with saturated brine (30 mL x 2). Dry the organic phase over anhydrous sodium sulfate, filter, concentrate under reduced pressure, purify the crude product by silica gel column chromatography (dichloromethane / ethyl acetate, 1 / 1, v / v) to obtain compound 10-2. ESI-MS Theoretical value: [M+H] = 349.15, Found 349.0. +

[0199] Second step

[0200] Dissolve compound 10-2 (250 mg, 0.72 mmol) in tetrahydrofuran (10 mL), drop in tetrahydroaluminum lithium solution in tetrahydrofuran (2.88 mL, 7.20 mmol, 2.5 mol / L) at 0 °C, stir the reaction solution at 60 °C for 16 h under nitrogen atmosphere. Cool the reaction solution to room temperature, quench with ice water (0.28 mL), add 15% sodium hydroxide aqueous solution (0.28 mL) and water (0.84 mL), filter, concentrate the filtrate under reduced pressure to obtain the crude product of the target compound, purify by high performance liquid chromatography (Waters-Agilent-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 21-27%, retention time: 9.1-11.3 min, run time: 18 min) to obtain compound 10. 1 ​H NMR (400 MHz, DMSO-d6): δ 10.85 (s, 1H), 7.07 (d, J = 2.0 Hz, 1H), 7.05 (d, J = 8.8 Hz, 1H), 6.93 (t, J = 8.4 Hz, 1H), 3.80 (s, 3H), 3.23-3.19 (m, 1H), 3.16-3.09 (m, 1H), 2.98-2.93 (m, 1H), 2.80-2.74 (m, 1H), 2.63-2.54 (m, 1H), 2.10 (s, 3H), 1.90-1.84 (m, 1H), 1.82-1.71 (m, 1H). ESI-MS Theoretical Calculation: [M+H] + = 249.13, found 249.0.

[0201] Example 11

[0202] Synthetic route:

[0203] First step

[0204] Compound 11-1 (12.5 g, 92.5 mmol) and pyridine (29.3 g, 370 mmol) were dissolved in dichloromethane (125 mL), and toluenesulfonyl chloride (19.4 g, 102 mmol) was added in batches at 0 °C, and the reaction solution was stirred at 25 °C for 16 hours. The reaction solution was added with water (250 mL), extracted with dichloromethane (250 mL x 3), and the combined organic phase was washed with saturated brine (200 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 11-2. 1 H NMR (400 MHz, CDCl3): δ 7.59 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H), 7.01 (s, 1H), 6.70-6.62 (m, 2H), 6.57 (d, J = 8.4 Hz, 1H), 4.54 (t, J = 8.8 Hz, 2H), 3.14 (t, J = 8.8 Hz, 2H), 2.38 (s, 3H). ESI-MS Theoretical Calculation: [M+Na] + = 312.08, found 312.2.

[0205] Second step

[0206] Compound 11-2 (15.0 g, 51.8 mmol), cesium carbonate (42.2 g, 130 mmol), potassium iodide (1.72 g, 10.4 mmol) and bromodiethyl acetal (102 g, 518 mmol) were dissolved in N,N-dimethylformamide (450 mL), and the reaction solution was stirred at 110°C for 16 hours. The reaction solution was cooled to room temperature, filtered, the filter cake was washed with ethyl acetate (500 mL), water (1000 mL) was added to the filtrate, and ethyl acetate (800 mL x 3) was extracted, and the combined organic phase was washed with saturated brine (500 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1, v / v) to obtain compound 11-3. 1 H NMR (400 MHz, CDC13): δ 7.50 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 7.00 (s, 1H), 6.62-6.56 (m, 2H), 4.61-4.55 (m, 3H), 3.67-3.59 (m, 2H), 3.58 (d, J = 5.6 Hz, 2H), 3.52-3.45 (m, 2H), 3.17 (t, J = 8.8 Hz, 2H), 2.42 (s, 3H), 1.14 (t, J = 7.2 Hz, 6H).

[0207] Third step

[0208] Compound 11-3 (10.5 g, 25.9 mmol) was dissolved in toluene (400 mL), and a solution of titanium tetrachloride (7.37 g, 38.8 mmol) dissolved in toluene (240 mL) was added dropwise at 110°C, and the reaction solution was stirred at 110°C for 1 hour. The reaction solution was cooled to room temperature, saturated aqueous sodium bicarbonate solution (400 mL) was added, and ethyl acetate (750 mL x 3) was extracted, and the combined organic phase was washed with saturated brine (500 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was dissolved in ethanol (75 mL), tetrahydrofuran (50 mL), and water (25 mL), and potassium hydroxide (16.3 g, 290 mmol) was added portionwise, and the reaction solution was stirred at 80°C for 16 hours. The reaction solution was cooled to room temperature, water (300 mL) was added, and ethyl acetate (300 mL x 3) was extracted, and the combined organic phase was washed with saturated brine (200 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 1, v / v) to obtain compound 11-4. 1H NMR (400 MHz, CDC13) δ 8.09 (s, 1H), 7.22 (t, J = 2.8 Hz, 1H), 7.16 (dd, J = 8.4, 0.8 Hz, 1H), 6.78 (d, J = 8.4 Hz, 1H), 6.37 (dd, J = 3.6, 1.6 Hz, 1H), 4.65 (t, J = 8.8 Hz, 2H), 3.38 (t, J = 8.8 Hz, 2H). ESI-MS Theoretical mass: [M+H] + = 160.07, found 160.0.

[0209] Fourth Step

[0210] (R)-N-carboxylic acid tert-butyl ester-azetidine-2-carboxylic acid (2.64 g, 13.1 mmol) was dissolved in dichloromethane (30 mL), oxalyl chloride (1.35 mL, 15.7 mmol) was added dropwise at 0 °C, the reaction solution was stirred at 0 °C for 10 min, N,N-dimethylformamide (96.0 mg, 1.39 mmol) was added slowly, the reaction solution was stirred at 25 °C for 1 h. The reaction solution was concentrated under reduced pressure to obtain the crude intermediate. Compound 11-4 (1.67 g, 10.5 mmol) was dissolved in dichloromethane (20 mL), ethyl magnesium bromide (5.51 mL, 11.0 mmol, 2 mol / L) was added dropwise slowly at 0 °C under nitrogen atmosphere, the reaction solution was stirred at 0 °C for 0.5 h. The crude intermediate was dissolved in dichloromethane (30 mL), added dropwise to the reaction solution at 0 °C, the reaction solution was stirred at 0 °C for 0.5 h. The reaction solution was added to saturated aqueous citric acid solution (50 mL), extracted with dichloromethane (50 mL x 3), the organic phase was combined and washed with saturated brine (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, the crude product was purified by silica gel column chromatography (dichloromethane / ethyl acetate, 1 / 1, v / v) to obtain compound 11-5. ESI-MS Theoretical mass: [M+H] + = 343.16, found 343.0.

[0211] Fifth Step

[0212] Compound 11-5 (263 mg, 0.77 mmol) was dissolved in tetrahydrofuran (10 mL), tetrahydroaluminum lithium solution in tetrahydrofuran (3.08 mL, 7.70 mmol, 2.5 mol / L) was added dropwise at 0 °C, the reaction solution was stirred at 60 °C for 16 h under nitrogen atmosphere. The reaction solution was cooled to room temperature, quenched by adding ice water (0.3 mL), added 15% sodium hydroxide aqueous solution (0.3 mL) and water (0.9 mL), filtered, the filtrate was concentrated under reduced pressure to obtain the crude product of the target compound, which was purified by silica gel column chromatography (dichloromethane / methanol, 9 / 1, v / v) to obtain compound 11. 1H NMR (400 MHz, DMSO-d6): δ 10.59 (s, 1H), 7.06-7.02 (m, 2H), 6.56 (d, J = 8.4 Hz, 1H), 4.51 (t, J = 8.8 Hz, 2H), 3.48-3.44 (m, 2H), 3.26-3.18 (m, 1H), 3.12-3.03 (m, 1H), 2.97-2.92 (m, 1H), 2.75-2.65 (m, 1H), 2.61-2.54 (m, 1H), 2.12 (s, 3H), 1.95-1.89 (m, 1H), 1.82-1.75 (m, 1H). ESI-MS Theoretical calculation value: [M+H] + = 243.14, found 243.0.

[0213] Example 12

[0214] Synthetic route:

[0215] First step

[0216] (R)-N-carboxylic acid tert-butyl ester-azetidine-2-carboxylic acid (3.30 g, 19.7 mmol) was dissolved in dichloromethane (40 mL), oxalyl chloride (1.69 mL, 19.6 mmol) was added dropwise at 0 °C, the reaction solution was stirred at 0 °C for 10 min, N,N-dimethylformamide (120 mg, 1.73 mmol) was slowly added, the reaction solution was stirred at 25 °C for 1 h. The reaction solution was concentrated under reduced pressure to obtain the crude intermediate. Compound 12-1 (2.00 g, 14.8 mmol) was dissolved in dichloromethane (20 mL), ethyl magnesium bromide (7.77 mL, 15.5 mmol, 2 mol / L) was slowly added dropwise at 0 °C under nitrogen atmosphere, and the reaction solution was stirred at 0 °C for 0.5 h. The crude intermediate was dissolved in dichloromethane (30 mL), which was added dropwise to the reaction solution at 0 °C, and the reaction solution was stirred at 0 °C for 0.5 h. The reaction solution was added to saturated aqueous citric acid solution (30 mL), extracted with dichloromethane (50 mL x 3), and the combined organic phase was washed with saturated brine (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / ethyl acetate, 1 / 1, v / v) to obtain compound 12-2. ESI-MS Theoretical calculation value: [M+H] + = 319.14, found 319.0.

[0217] Second step

[0218] Compound 12-2 (80.0 mg, 0.25 mmol) was dissolved in tetrahydrofuran (10 mL), tetrahydroaluminum lithium solution in tetrahydrofuran (1 mL, 2.50 mmol, 2.5 mol / L) was added dropwise at 0 °C, the reaction solution was stirred at 60 °C for 16 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, ice water (0.1 mL) was added to quench, 15% sodium hydroxide aqueous solution (0.1 mL) and water (0.3 mL) were added, filtered, the filtrate was concentrated under reduced pressure to obtain the crude product of the target compound, which was purified by high performance liquid chromatography (Waters-Agilent-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 26-37%, retention time: 10.2-11.8 min, running time: 18 min) to obtain compound 12. 1 H NMR (400 MHz, DMSO-d6): δ 10.84 (s, 1H), 7.50 (dd, J = 8.4, 5.6 Hz, 1H), 7.11-7.07 (m, 2H), 6.82 (t, J = 8.4 Hz, 1H), 3.22 (t, J = 6.4 Hz, 1H), 3.13-3.06 (m, 1H), 2.91-2.86 (m, 1H), 2.75-2.70 (m, 1H), 2.62-2.56 (m, 1H), 2.10 (s, 3H), 1.96-1.85 (m, 1H), 1.80-1.72 (m, 1H). ESI-MS Theoretical calculation value: [M+H] + = 219.12, found 219.0.

[0219] Example 13

[0220] Synthetic route:

[0221] First step

[0222] Dissolve (R)-N-carboxylic acid tert-butyl ester-azetidine-2-carboxylic acid (1.32 g, 6.55 mmol) in dichloromethane (20 mL), drop in oxalyl chloride (0.675 mL, 7.85 mmol) at 0 °C, stir the reaction solution at 0 °C for 10 min, slowly add N,N-dimethylformamide (48.0 mg, 0.693 mmol), stir the reaction solution at 25 °C for 1 h. Concentrate the reaction solution under reduced pressure to obtain the crude intermediate. Dissolve compound 13-1 (1.00 g, 5.71 mmol) in dichloromethane (15 mL), slowly drop in ethyl magnesium bromide (3.00 mL, 6.00 mmol, 2 mol / L) under nitrogen atmosphere at 0 °C, stir the reaction solution at 0 °C for 0.5 h. Dissolve the crude intermediate in dichloromethane (20 mL), drop into the reaction solution at 0 °C, stir the reaction solution at 0 °C for 0.5 h. Add saturated aqueous citric acid solution (30 mL) to the reaction solution, extract with dichloromethane (30 mL x 3), combine the organic phases, wash with saturated brine (30 mL x 2). Dry the organic phase over anhydrous sodium sulfate, filter, concentrate under reduced pressure, purify the crude product by silica gel column chromatography (dichloromethane / ethyl acetate, 1 / 1, v / v) to obtain compound 13-2. ESI-MS Theoretical value: [M+H] = 359.19, Found 359.0. +

[0223] Second step

[0224] Dissolve compound 13-2 (100 mg, 0.28 mmol) in tetrahydrofuran (5 mL), drop in tetrahydrofuran solution of lithium aluminum hydride (1.12 mL, 5.00 mmol, 2.5 mol / L) at 0 °C, stir the reaction solution at 60 °C for 16 h under nitrogen atmosphere. Cool the reaction solution to room temperature, quench with ice water (0.12 mL), add 15% aqueous sodium hydroxide solution (0.12 mL) and water (0.36 mL), filter, concentrate the filtrate under reduced pressure to obtain the crude product of the target compound, purify by high performance liquid chromatography (Waters-Agilent-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L aqueous ammonium bicarbonate solution, gradient: 24-33%, retention time: 8.45-10.35 min, run time: 16 min) to obtain compound 13. 1 ​H NMR (400 MHz, DMSO-d6): δ 10.58 (s, 1H), 7.18 (d, J = 8.8 Hz, 1H), 7.03 (d, J = 2.0 Hz, 1H), 6.99 (d, J = 2.0 Hz, 1H), 6.68 (dd, J = 8.8, 2.4 Hz, 1H), 4.54-4.46 (m, 1H), 3.25-3.19 (m, 1H), 3.11-3.04 (m, 1H), 2.88-2.80 (m, 1H), 2.73-2.66 (m, 1H), 2.62-2.57 (m, 1H), 2.11 (s, 3H), 1.95-1.88 (m, 1H), 1.82-1.75 (m, 1H), 1.25 (d, J = 6.0 Hz, 6H). ESI-MS Theoretical mass: [M+H] = 259.17, found 259.0. + = 259.17, found 259.0.

[0225] Example 14

[0226] Synthetic route:

[0227] First step

[0228] Compound 14-1 (700 mg, 3.08 mmol) was dissolved in dichloromethane (10 mL), triethylamine (620 mg, 6.16 mmol), di-tert-butyl dicarbonate (810 mg, 3.70 mmol) and 4-dimethylaminopyridine (38.0 mg, 0.31 mmol) were added, and stirred at 25 °C for 4 hours. The reaction solution was added to saturated aqueous ammonium chloride solution (20 mL), extracted with dichloromethane (20 mL x 3), and the combined organic phases were washed with saturated brine (30 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1, v / v) to obtain compound 14-2. 1 H NMR (400 MHz, DMSO-d6): δ 8.00 (d, J = 9.2 Hz, 1H), 7.33 (dd, J = 9.2, 2.4 Hz, 1H), 7.06 (d, J = 2.4 Hz, 1H), 3.88 (s, 3H), 1.64 (s, 9H).

[0229] Second step

[0230] In a glove box filled with nitrogen, compound 14-2 (196 mg, 0.60 mmol), (2R)-2- (bromomethyl)azetidine-1-carboxylate tert-butyl ester (100 mg, 0.40 mmol), anhydrous sodium carbonate (84.8 mg, 0.80 mmol), tris(trimethylsilyl)silane (99.5 mg, 0.40 mmol), nickel chloride dimethoxyethane (4.4 mg, 0.02 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (5.4 mg, 0.02 mmol) and bis[2-(2,4-difluorophenyl)-5- trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium dimethyl phosphate (4.5 mg, 0.004 mmol) were dissolved in ethylene glycol dimethyl ether (6 mL). The reaction was placed under 34 W blue LED (420 nm) irradiation at 25 °C and stirred for 16 hours. After the reaction was completed, the blue light was turned off, the reaction was added to water (20 mL), extracted with dichloromethane (20 mL x 3), and the organic phase was combined and washed with saturated brine (30 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 2 / 1, v / v) to obtain compound 14-3. ESI-MS Theoretical calculation: [M+H] + = 418.23, found 418.0.

[0231] Third step

[0232] Compound 14-3 (200 mg, 0.48 mmol) was dissolved in 1,2-dichloromethane (5 mL), and trifluoroacetic acid (1.5 mL) was added to the reaction. The reaction was stirred at 25 °C for 0.5 hours. After the reaction was completed, it was concentrated under reduced pressure to obtain compound 14-4. ESI-MS Theoretical calculation: [M+H] + = 218.12, found 218.0.

[0233] Fourth step

[0234] Compound 14-4 (104 mg, 0.48 mmol) was dissolved in methanol (5 mL), triethylamine (150 mg, 1.44 mmol) and paraformaldehyde (42.9 mg, 0.53 mmol) were added into the reaction solution, the reaction solution was stirred at 25 °C for 0.5 h, sodium cyanoborohydride (18.1 mg, 0.29 mmol) was added, the reaction solution was stirred at 25 °C for 2 h. The reaction solution was added into saturated aqueous sodium bicarbonate solution (5 mL), extracted with dichloromethane (10 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, the crude product was purified by high performance liquid chromatography (Waters-Agilent-C18-10 μm-19*250 mm, mobile phase: acetonitrile-0.1% formic acid aqueous solution, gradient: 7-17%, retention time: 9.5-10.1 min, run time: 16 min) to obtain monohydrochloride of compound 14. 1 H NMR (400 MHz, DMSO-d6): δ 12.81 (s, 1H), 9.81 (s, 1H), 7.42 (d, J = 8.8 Hz, 1H), 7.22 (s, 1H), 7.03 (dd, J = 8.8, 2.0 Hz, 1H), 4.73-4.64 (m, 1H), 4.08-3.99 (m, 1H), 3.87-3.76 (m, 4H), 3.57-3.52 (m, 1H), 3.45-3.38 (m, 1H), 2.76 (s, 3H), 2.46-2.41 (m, 1H), 2.35-2.28 (m, 1H). ESI-MS Theoretical calculation: [M+H] + = 232.14, found 232.0.

[0235] Example 15

[0236] Synthetic route:

[0237] First step

[0238] Dissolve (R)-N-carboxylic acid tert-butyl ester-azetidine-2-carboxylic acid (5.28 g, 26.2 mmol) in dichloromethane (100 mL), drop in oxalyl chloride (2.70 mL, 31.4 mmol) at 0 °C, stir the reaction solution at 0 °C for 10 min, slowly add N,N-dimethylformamide (192 mg, 2.77 mmol), stir the reaction solution at 25 °C for 1 h. Concentrate the reaction solution under reduced pressure to obtain the crude intermediate. Dissolve compound 15-1 (3.10 g, 20.2 mmol) in dichloromethane (30 mL), slowly drop in ethyl magnesium bromide (10.6 mL, 21.3 mmol, 2 mol / L) under nitrogen atmosphere at 0 °C, stir at 0 °C for 0.5 h. Dissolve the crude intermediate in dichloromethane (50 mL), drop into the reaction solution at 0 °C, stir the reaction solution at 0 °C for 0.5 h. Add saturated aqueous citric acid solution (200 mL) to the reaction solution, extract with dichloromethane (200 mL x 3), combine the organic phases, wash with saturated brine (200 mL x 2). Dry the organic phase over anhydrous sodium sulfate, filter, concentrate under reduced pressure, purify the crude product by silica gel column chromatography (dichloromethane / ethyl acetate, 1 / 1, v / v) to obtain compound 15-2. ESI-MS Theoretical value: [M+H] = 337.13, Found 336.9. +

[0239] Second step

[0240] Dissolve compound 15-2 (690 mg, 2.05 mmol) in tetrahydrofuran (20 mL), drop in tetrahydrofuran solution of lithium aluminum hydride (8.20 mL, 20.5 mmol, 2.5 mol / L) at 0 °C, stir the reaction solution at 60 °C for 16 h under nitrogen atmosphere. Cool the reaction solution to room temperature, quench with ice water (0.8 mL), add 15% aqueous sodium hydroxide solution (0.8 mL) and water (2.4 mL), filter, concentrate the filtrate under reduced pressure to obtain the crude product of the target compound, purify by high performance liquid chromatography (Waters-Agilent-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L aqueous ammonium bicarbonate solution, gradient: 20-45%, retention time: 7.5-9.2 min, run time: 16 min) to obtain compound 15. 1 ​H NMR (400 MHz, DMSO-d6): δ 11.16 (s, 1H), 7.11 (s, 1H), 6.97 (dd, J = 9.6, 2.0 Hz, 1H), 6.75-6.68 (m, 1H), 3.23-3.19 (m, 1H), 3.16-3.11 (m, 1H), 2.97-2.92 (m, 1H), 2.80-2.75 (m, 1H), 2.64-2.58 (m, 1H), 2.09 (s, 3H), 1.92-1.84 (m, 1H), 1.80-1.73 (m, 1H). ESI-MS Theoretical Calculation: [M+H] + = 237.11, found 237.0.

[0241] Example 16

[0242] Synthetic route:

[0243] First step

[0244] Compound 16-1 (4.18 g, 19.2 mmol) was dissolved in tetrahydrofuran (38 mL) and water (38 mL), and lithium hydroxide monohydrate (2.42 g, 57.72 mmol) was added. The reaction solution was stirred at 25 °C for 16 hours. The reaction solution was added to 1 mol / L aqueous hydrochloric acid solution, and the pH was adjusted to 4. Ethyl acetate (100 mL x 4) was added for extraction, and the organic phase was combined and washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 1, v / v) to obtain compound 16-2. 1 H NMR (400 MHz, DMSO-d6): δ 12.89 (s, 1H), 11.71 (s, 1H), 7.11 (d, J = 8.4 Hz, 1H), 6.92 (dd, J = 8.4, 0.8 Hz, 1H), 6.89 (d, J = 2.0 Hz, 1H), 4.64 (t, J = 8.8 Hz, 2H), 3.21 (t, J = 8.8 Hz, 2H). ESI-MS Theoretical Calculation: [M+H] + = 204.06, found 204.0.

[0245] Second step

[0246] Compound 16-2 (4.00 g, 19.7 mmol) was dissolved in quinoline (32 mL), copper oxide (470 mg, 5.91 mmol) was added, and the reaction was stirred at 200 °C for 2 h. The reaction was cooled to room temperature, and the pH was adjusted to 4 by adding 1 mol / L aqueous hydrochloric acid solution. The reaction was extracted with ethyl acetate (100 mL x 3), and the organic phase was combined and washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1, v / v) to obtain compound 16-3. 1 H NMR (400 MHz, DMSO-d6): δ 11.02 (s, 1H), 7.21 (s, 1H), 6.94 (d, J = 8.0 Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H), 6.26 (s, 1H), 4.59 (t, J = 8.8 Hz, 2H), 3.20 (t, J = 8.8 Hz, 2H). ESI-MS Theoretical calculation: [M+H] + = 160.07, found 160.0.

[0247] Third step

[0248] (R)-N-carboxylic acid tert-butyl ester-azetidine-2-carboxylic acid (2.64 g, 13.1 mmol) was dissolved in dichloromethane (50 mL), and oxalyl chloride (1.35 mL, 15.7 mmol) was added dropwise at 0 °C. The reaction was stirred at 0 °C for 10 min, and N,N-dimethylformamide (96.0 mg, 1.39 mmol) was slowly added. The reaction was stirred at 25 °C for 1 h. The reaction was concentrated under reduced pressure to obtain a crude intermediate. Compound 16-3 (1.50 g, 9.42 mmol) was dissolved in dichloromethane (15 mL), and ethyl magnesium bromide (4.95 mL, 9.89 mmol, 2 mol / L) was slowly added dropwise at 0 °C under a nitrogen atmosphere. The reaction was stirred at 0 °C for 0.5 h. The crude intermediate was dissolved in dichloromethane (50 mL), and the reaction was added dropwise at 0 °C. The reaction was stirred at 0 °C for 0.5 h. The reaction was added with saturated aqueous citric acid solution (100 mL), and dichloromethane (50 mL x 3) was added to extract the organic phase. The organic phase was combined and washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / ethyl acetate, 1 / 1, v / v) to obtain compound 16-4. ESI-MS Theoretical calculation: [M+H] + = 343.16, found 343.2.

[0249] Fourth step

[0250] Compound 16-4 (165 mg, 0.48 mmol) was dissolved in tetrahydrofuran (4 mL), tetrahydroaluminum lithium solution in tetrahydrofuran (2.88 mL, 7.20 mmol, 2.5 mol / L) was added dropwise at 0 °C, the reaction solution was stirred at 60 °C for 16 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, quenched by adding ice water (0.28 mL), 15% sodium hydroxide aqueous solution (0.28 mL) and water (0.84 mL) were added, filtered, the filtrate was concentrated under reduced pressure to obtain the crude product of the target compound, which was purified by high performance liquid chromatography (Waters-Agilent-C18-10 μm-19*250 mm, mobile phase: acetonitrile-0.1% methanolic acid aqueous solution, gradient: 10-20%, retention time: 7.1-10.0 min, running time: 17 min) to obtain the monomethanolic acid salt of compound 16. 1 H NMR (400 MHz, DMSO-d6): δ 10.75 (s, 1H), 8.30 (s, 1H), 6.99 (s, 1H), 6.90 (d, J = 8.0 Hz, 1H), 6.80 (d, J = 8.0 Hz, 1H), 4.61 (t, J = 8.8 Hz, 2H), 3.60-3.56 (m, 1H), 3.47-3.43 (m, 1H), 3.17 (t, J = 8.8 Hz, 2H), 3.09-3.03 (m, 1H), 2.97-2.85 (m, 2H), 2.24 (s, 3H), 2.00-1.92 (m, 2H). ESI-MS Theoretical calculation value: [M+H] + = 243.14, found 243.0.

[0251] Example 17

[0252] Synthetic route:

[0253] First step

[0254] Dissolve (R)-N-carboxylic acid tert-butyl ester-azetidine-2-carboxylic acid (1.32 g, 6.55 mmol) in dichloromethane (20 mL), drop in oxalyl chloride (0.675 mL, 7.85 mmol) at 0 °C, stir the reaction solution at 0 °C for 10 min, slowly add N,N-dimethylformamide (48.0 mg, 0.695 mmol), stir the reaction solution at 25 °C for 1 h. Concentrate the reaction solution under reduced pressure to obtain the crude intermediate. Dissolve compound 17-1 (900 mg, 5.20 mmol) in dichloromethane (15 mL), slowly drop in ethyl magnesium bromide (2.73 mL, 5.46 mmol, 2 mol / L) under nitrogen atmosphere at 0 °C, stir the reaction solution at 0 °C for 0.5 h. Dissolve the crude intermediate in dichloromethane (20 mL), drop into the reaction solution at 0 °C, stir the reaction solution at 0 °C for 0.5 h. Add saturated aqueous citric acid solution (50 mL) to the reaction solution, extract with dichloromethane (50 mL x 3), combine the organic phases, wash with saturated brine (50 mL). Dry the organic phase over anhydrous sodium sulfate, filter, concentrate under reduced pressure, purify the crude product by silica gel column chromatography (dichloromethane / ethyl acetate, 1 / 1, v / v) to obtain compound 17-2. ESI-MS Theoretical value: [M+H] = 357.17, Found 356.9. +

[0255] Second step

[0256] Dissolve compound 17-2 (320 mg, 0.90 mmol) in tetrahydrofuran (10 mL), drop in tetrahydrofuran solution of lithium aluminum hydride (3.60 mL, 9.00 mmol, 2.5 mol / L) at 0 °C, stir the reaction solution at 60 °C for 16 h under nitrogen atmosphere. Cool the reaction solution to room temperature, quench with ice water (0.36 mL), add 15% aqueous sodium hydroxide solution (0.36 mL) and water (1.08 mL), filter, concentrate the filtrate under reduced pressure to obtain the crude product of the target compound, purify by high performance liquid chromatography (Waters-Agilent-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L aqueous ammonium bicarbonate solution, gradient: 15-45%, retention time: 8.8-10.2 min, run time: 16 min) to obtain compound 17. 1 ​H NMR (400 MHz, DMSO-d6): δ 10.56 (s, 1H), 7.00 (d, J = 8.4 Hz, 1H), 6.94 (d, J = 2.4 Hz, 1H), 6.48 (d, J = 8.4 Hz, 1H), 4.07-4.04 (m, 2H), 3.26-3.23 (m, 1H), 3.18-3.04 (m, 4H), 2.86-2.78 (m, 1H), 2.64-2.57 (m, 1H), 2.12 (s, 3H), 2.00-1.94 (m, 3H), 1.79-1.75 (m, 1H). ESI-MS Theoretical Calculation: [M+H] + = 257.16, found 257.1.

[0257] Example 18

[0258] Synthetic route:

[0259] First step

[0260] Compound 18-1 (4.00 g, 28.1 mmol) was dissolved in N,N-dimethylformamide (80 mL), N-bromosuccinimide (5.01 g, 28.1 mmol) was added slowly at 0 °C under nitrogen atmosphere, and stirred at 25 °C for 16 hours. The reaction solution was added with water (100 mL), extracted with ethyl acetate (200 mL x 3), and the combined organic phase was washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / dichloromethane, 1 / 1, v / v) to obtain compound 18-2. 1 H NMR (400 MHz, DMSO-d6): δ 12.04 (s, 1H), 7.91 (s, 1H), 7.79 (s, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H).

[0261] Second step

[0262] Compound 18-2 (4.70 g, 21.3 mmol) was dissolved in N,N-dimethylformamide (90 mL), sodium hydride (1.02 g, 25.5 mmol, 60% purity) was slowly added at 0 °C under nitrogen atmosphere, stirred at 0 °C for 0.5 h, p-toluenesulfonyl chloride (4.46 g, 23.4 mmol) was added, stirred at 25 °C for 12 h. The reaction solution was added to saturated aqueous ammonium chloride solution (100 mL), extracted with ethyl acetate (100 mL x 3), the combined organic phase was washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, the crude product was purified by silica gel column chromatography (petroleum ether / dichloromethane, 4 / 1, v / v) to obtain compound 18-3. 1 H NMR (400 MHz, DMSO-d6): δ 8.38 (s, 1H), 8.16 (d, J = 8.4 Hz, 1H), 8.04 (d, J = 1.2 Hz, 1H), 7.98 (d, J = 8.4 Hz, 2H), 7.85 (dd, J = 8.4, 1.2 Hz, 1H), 7.43 (d, J = 8.4 Hz, 2H), 2.33 (s, 3H).

[0263] Third step

[0264] In a glove box filled with nitrogen, compound 18-3 (200 mg, 0.53 mmol), (2R)-2- (bromomethyl)azetidine-1-carboxylate tert-butyl ester (199 mg, 0.80 mmol), anhydrous sodium carbonate (110 mg, 1.06 mmol), tris(trimethylsilyl)silane (197 mg, 0.80 mmol), nickel chloride dimethyl oxide (5.8 mg, 0.027 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (7.1 mg, 0.027 mmol) and bis[2-(2,4-difluorophenyl)-5- trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium bis(hexafluorophosphate) (6.0 mg, 0.0053 mmol) were dissolved in ethylene glycol dimethyl ether (4 mL). The reaction solution was placed under 34 W blue LED (420 nm) irradiation and stirred at 25 °C for 16 h. After the reaction was completed, the blue light was turned off, the reaction solution was added to water (20 mL), extracted with dichloromethane (20 mL x 3), the combined organic phase was washed with saturated brine (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 2 / 1, v / v) to obtain compound 18-4. ESI-MS Theoretical calculation: [M+H-56] + = 410.17, found 410.0.

[0265] Fourth step

[0266] Compound 18-4 (160 mg, 0.34 mmol) was dissolved in 1,2-dichloromethane (5 mL), trifluoroacetic acid (1.0 mL) was added into the reaction solution, the reaction solution was stirred at 25 °C for 1 hour. After the reaction was completed, it was concentrated under reduced pressure to obtain compound 18-5. ESI-MS Theoretical value: [M+H]=366.12, Found 366.4. +

[0267] Fifth step

[0268] Compound 18-5 (125 mg, 0.34 mmol) was dissolved in methanol (5 mL), diisopropylethylamine (132 mg, 1.02 mmol) and paraformaldehyde (55.2 mg, 0.68 mmol) were added into the reaction solution, the reaction solution was stirred at 25 °C for 0.5 hour, sodium cyanoborohydride (32.1 mg, 0.51 mmol) was added, the reaction solution was stirred at 25 °C for 2 hours. The reaction solution was added with saturated aqueous sodium bicarbonate solution (5 mL), extracted with ethyl acetate (10 mL x 3), the organic phase was combined, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was dissolved in tetrahydrofuran (0.4 mL), ethanol (2.0 mL) and water (2.0 mL), lithium hydroxide monohydrate (54.0 mg, 1.28 mmol) was added, the reaction solution was stirred at 70 °C for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the crude product was purified by high performance liquid chromatography (Waters-Agilent-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 17-33%, retention time: 9.0-10.7 min, running time: 16 min) to obtain compound 18. 1 H NMR (400 MHz, DMSO-d6): δ 11.40 (s, 1H), 8.09 (s, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.39 (dd, J = 8.4, 1.2 Hz, 1H), 7.33 (s, 1H), 3.24-3.20 (m, 1H), 3.13-3.07 (m, 1H), 2.96-2.91 (m, 1H), 2.81-2.76 (m, 1H), 2.63-2.59 (m, 1H), 2.09 (s, 3H), 1.94-1.87 (m, 1H), 1.83-1.74 (m, 1H). ESI-MS Theoretical value: [M+H]=226.13, Found 226.0. +

[0269] Example 19

[0270] Synthetic route:

[0271] First step​​

[0272] Compound 19-2 (4.30 g, 18.9 mmol) was dissolved in N,N-dimethylformamide (40 mL), sodium hydride (909 mg, 22.7 mmol, 60% purity) was added slowly at 0 °C under nitrogen atmosphere, stirred at 0 °C for 0.5 h, p-toluenesulfonyl chloride (4.33 g, 22.7 mmol) was added, stirred at 25 °C for 0.5 h. The reaction solution was added to saturated aqueous ammonium chloride solution (100 mL), extracted with ethyl acetate (100 mL x 3), the organic phases were combined and washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / dichloromethane, 4 / 1, v / v) to obtain compound 19-3. 1 H NMR (400 MHz, DMSO-d6): δ 11.53 (s, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.66 (s, 1H), 6.63 (d, J = 8.8 Hz, 1H), 3.89 (s, 3H).

[0273] Second step

[0274] Compound 19-2 (4.30 g, 18.9 mmol) was dissolved in N,N-dimethylformamide (40 mL), sodium hydride (909 mg, 22.7 mmol, 60% purity) was added slowly at 0 °C under nitrogen atmosphere, stirred at 0 °C for 0.5 h, p-toluenesulfonyl chloride (4.33 g, 22.7 mmol) was added, stirred at 25 °C for 0.5 h. The reaction solution was added to saturated aqueous ammonium chloride solution (100 mL), extracted with ethyl acetate (100 mL x 3), the organic phases were combined and washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / dichloromethane, 4 / 1, v / v) to obtain compound 19-3. 1 H NMR (400 MHz, DMSO-d6): δ 11.53 (s, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.66 (s, 1H), 6.63 (d, J = 8.8 Hz, 1H), 3.89 (s, 3H).

[0275] Third step

[0276] In a glove box filled with nitrogen, compound 19-3 (200 mg, 0.52 mmol), (2R)-2- (bromomethyl)azetidine-1-carboxylate (195 mg, 0.78 mmol), anhydrous sodium carbonate (110 mg, 1.04 mmol), tris(trimethylsilyl)silane (194 mg, 0.78 mmol), nickel chloride dimethoxyethane (5.7 mg, 0.026 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (7.0 mg, 0.026 mmol) and bis[2-(2,4-difluorophenyl)-5- trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium bis(hexafluorophosphate) (5.8 mg, 0.0052 mmol) were dissolved in ethylene glycol dimethyl ether (4 mL). The reaction was placed under 34 W blue LED (420 nm) irradiation and stirred at 25 °C for 16 h. After the reaction was completed, the blue light was turned off, the reaction was added with water (20 mL), dichloromethane (20 mL x 3) was extracted, the organic phase was combined and washed with saturated brine (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 2 / 1, v / v) to obtain compound 19-4. ESI-MS Theoretical calculation: [M+H] = 472.18, found 472.0. +

[0277] Fourth step

[0278] Compound 19-4 (230 mg, 0.49 mol) was dissolved in anhydrous tetrahydrofuran (5 mL), anhydrous ethanol (5 mL) and water (2 mL), sodium hydroxide (58.8 mg, 1.47 mmol) was added, and the reaction was stirred at 60 °C for 4 h. The reaction was added with water (20 mL), dichloromethane (20 mL x 3) was extracted, the organic phase was combined and washed with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane / methanol, 10 / 1, v / v) to obtain compound 19-5. ESI-MS Theoretical calculation: [M+H] = 318.17, found 318.5. +

[0279] Fifth step

[0280] ​​Compound 19-5 (70.0 mg, 0.22 mmol) was dissolved in tetrahydrofuran (3 mL), and a tetrahydroaluminum lithium solution in tetrahydrofuran (0.44 mL, 1.10 mmol, 2.5 mol / L) was added dropwise at 0 °C. The reaction solution was stirred at 60 °C for 2 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, quenched by adding ice water (0.05 mL), and then 15% sodium hydroxide aqueous solution (0.05 mL) and water (0.15 mL) were added. Filtration was performed, and the filtrate was concentrated under reduced pressure to obtain a crude product of the target compound. Purification by high performance liquid chromatography (Waters-Agilent-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 15-43%, retention time: 6.9-8.5 min, run time: 16 min) yielded compound 19. 1 H NMR (400 MHz, DMSO-d6): δ 10.81 (s, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 2.4 Hz, 1H), 6.49 (d, J = 8.4 Hz, 1H), 3.87 (s, 3H), 3.24-3.20 (m, 2H), 2.92-2.85 (m, 1H), 2.80-2.73 (m, 1H), 2.61-2.56 (m, 1H), 2.14 (s, 3H), 1.92-1.79 (m, 2H). ESI-MS Theoretical calculation: [M+H] = 232.14, found 232.2. + = 232.14, found 232.2.

[0281] Example 20

[0282] Synthetic route:

[0283] First step

[0284] Compound 20-1 (2.00 g, 10.2 mmol) was dissolved in N,N-dimethylformamide (20 mL), and N-bromosuccinimide (1.91 g, 10.8 mmol) was slowly added at 0 °C under a nitrogen atmosphere. The reaction solution was stirred at 25 °C for 2 hours. Water (50 mL) was added to the reaction solution, and extraction was performed with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification of the crude product by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) yielded compound 20-2. 1 H NMR (400 MHz, DMSO-d6): δ 7.98 (s, 1H), 7.82 (s, 1H), 7.74-7.64 (m, 2H), 3.20 (s, 3H).

[0285] Second step

[0286] Compound 20-2 (2.40 g, 8.75 mmol) was dissolved in N,N-dimethylformamide (40 mL), sodium hydride (420 mg, 10.5 mmol, 60% purity) was added slowly at 0 °C under nitrogen atmosphere, stirred at 0 °C for 0.5 h, p-toluenesulfonyl chloride (1.84 g, 9.63 mmol) was added, stirred at 25 °C for 1 h. The reaction solution was added to saturated aqueous ammonium chloride solution (100 mL), extracted with ethyl acetate (100 mL x 3), the combined organic phase was washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, the crude product was purified by silica gel column chromatography (petroleum ether / dichloromethane, 4 / 1, v / v) to obtain compound 20-3. 1 H NMR (400 MHz, CDCl3): δ 8.16 (d, J = 8.8 Hz, 2H), 7.92 (dd, J = 8.8, 1.6 Hz, 1H), 7.82-7.75 (m, 3H), 7.29 (d, J = 8.8 Hz, 2H), 3.08 (s, 3H), 2.38 (s, 3H).

[0287] Third step

[0288] Compound 20-3 (200 mg, 0.47 mmol), (2R)-2-(bromomethyl)azetidine-1-carboxylate (175 mg, 0.70 mmol), anhydrous sodium carbonate (99.6 mg, 0.94 mmol), tris(trimethylsilyl)silane (175 mg, 0.70 mmol), nickel chloride dimethyl oxide (5.2 mg, 0.024 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (6.3 mg, 0.024 mmol) and bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium dimethyl phosphate (5.2 mg, 0.0047 mmol) were dissolved in ethylene glycol dimethyl ether (5 mL) in a nitrogen-filled glove box. The reaction solution was placed under 34 W blue LED (420 nm) irradiation and stirred at 25 °C for 16 h. After the reaction was completed, the blue light was turned off, the reaction solution was added to water (20 mL), extracted with dichloromethane (20 mL x 3), the combined organic phase was washed with saturated brine (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 1, v / v) to obtain compound 20-4. ESI-MS Theoretical value: [M+H-56] = 463.15, Found 463.1. +

[0289] Fourth step

[0290] ​Compound 20-4 (350 mg, 0.67 mol) was dissolved in anhydrous tetrahydrofuran (1.5 mL), anhydrous ethanol (1.5 mL) and water (0.6 mL), lithium hydroxide monohydrate (141 mg, 3.35 mmol) was added, and the reaction was stirred at 60 °C for 3 hours. The reaction was added with water (20 mL), extracted with dichloromethane (20 mL x 3), and the organic phase was combined and washed with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain compound 20-5. ESI-MS Theoretical value: [M+H-56] + = 309.15, found 309.0.

[0291] Fifth step

[0292] Compound 20-5 (70.0 mg, 0.22 mmol) was dissolved in tetrahydrofuran (3 mL), and a tetrahydro-lithium aluminum solution in tetrahydrofuran (0.44 mL, 1.10 mmol, 2.5 mol / L) was added dropwise at 0 °C. The reaction was stirred at 60 °C for 2 hours under a nitrogen atmosphere. The reaction was cooled to room temperature, quenched with ice water (0.05 mL), and added with 15% sodium hydroxide aqueous solution (0.05 mL) and water (0.15 mL). The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of the target compound. The crude product was purified by high performance liquid chromatography (Waters-Agilent-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 20-25%, retention time: 6.0-7.0 min, run time: 16 min) to obtain compound 20. 1 H NMR (400 MHz, DMSO-d6): δ 11.40 (s, 1H), 8.13 (d, J = 1.2 Hz, 1H), 7.59-7.52 (m, 2H), 7.36 (s, 1H), 3.27-3.22 (m, 1H), 3.17-3.11 (m, 4H), 2.99-2.94 (m, 1H), 2.86-2.79 (m, 1H), 2.64-2.58 (m, 1H), 2.09 (s, 3H), 1.96-1.91 (m, 1H), 1.81-1.76 (m, 1H). ESI-MS Theoretical value: [M+H] + = 279.11, found 279.0.

[0293] Example 21

[0294] Synthetic route:

[0295] First step

[0296] Compound 21-1 (1.50 g, 6.97 mmol) was dissolved in N,N-dimethylformamide (15 mL), N-bromosuccinimide (1.24 g, 6.97 mmol) was added slowly at 0 °C under nitrogen atmosphere, and stirred at 25 °C for 2 hours. The reaction solution was added to water (20 mL), extracted with ethyl acetate (50 mL x 3), and the combined organic phase was washed with saturated brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain compound 21-2. ESI-MS Theoretical value: [M+H] = 293.97 and 295.97, Found 294.0 and 296.0. +

[0297] Second step

[0298] Compound 21-2 (2.29 g, 6.62 mmol) was dissolved in N,N-dimethylformamide (20 mL), and sodium hydride (320 mg, 7.94 mmol, 60% purity) was added slowly at 0 °C under nitrogen atmosphere. After stirring at 0 °C for 0.5 hours, p-toluenesulfonyl chloride (1.51 g, 7.94 mmol) was added, and stirred at 25 °C for 3 hours. The reaction solution was added to saturated aqueous ammonium chloride solution (20 mL), extracted with ethyl acetate (50 mL x 3), and the combined organic phase was washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1, v / v) to obtain compound 21-3. 1 H NMR (400 MHz, DMSO-d6): δ 8.13 (s, 1H), 7.93-7.88 (m, 3H), 7.40 (d, J = 8.0 Hz, 2H), 7.15 (dd, J = 8.8, 2.4 Hz, 1H), 7.08 (d, J = 2.4 Hz, 1H), 4.83 (q, J = 8.8 Hz, 2H), 2.32 (s, 3H).

[0299] Third step

[0300] ​In a glove box filled with nitrogen, compound 21-3 (350 mg, 0.78 mmol), (2R)-2- (bromomethyl)azetidine-1-carboxylate tert-butyl ester (292 mg, 1.17 mmol), anhydrous sodium carbonate (166 mg, 1.56 mmol), tris(trimethylsilyl)silane (290 mg, 1.56 mmol), nickel chloride dimethoxyethane (8.6 mg, 0.04 mmol), 4,4'-di-tert-butyl-2,2'- bipyridine (10.4 mg, 0.04 mmol) and bis[2-(2,4-difluorophenyl)-5- trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium dimethylphosphate (8.8 mg, 0.0078 mmol) were dissolved in ethylene glycol dimethyl ether (10 mL). The reaction was placed under 34 W blue LED (420 nm) irradiation and stirred at 25 °C for 16 hours. After the reaction was completed, the blue light was turned off, the reaction was added to water (50 mL), dichloromethane (50 mL x 3) was extracted, the organic phase was combined and washed with saturated brine (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 2 / 1, v / v) to obtain compound 21-4. ESI-MS Theoretical calculation: [M+H] = 539.17, found 539.3. +

[0301] Fourth step

[0302] Compound 21-4 (450 mg, 0.84 mmol) was dissolved in 1,2-dichloromethane (10 mL), and trifluoroacetic acid (4 mL) was added to the reaction. The reaction was stirred at 25 °C for 1 hour. After the reaction was completed, it was concentrated under reduced pressure, and the residue was dissolved in 1,2-dichloroethane (10 mL). Triethylamine (249 mg, 2.46 mmol) and 37% aqueous formaldehyde solution (200 mg, 2.46 mmol) were added to the reaction, which was stirred at 25 °C for 0.5 hours. Sodium triacetylboration hydride (348 mg, 1.64 mmol) was added, and the reaction was stirred at 25 °C for 2 hours. The reaction was added to saturated aqueous sodium bicarbonate solution (30 mL) and dichloromethane (30 mL x 3) was extracted. The organic phase was combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol, 20 / 1, v / v) to obtain compound 21-5. ESI-MS Theoretical calculation: [M+H] = 453.14, found 453.5. +

[0303] Fifth step

[0304] ​​Compound 21-5 (310 mg, 0.69 mol) was dissolved in anhydrous tetrahydrofuran (3 mL), anhydrous ethanol (3 mL) and water (3 mL), sodium hydroxide (138 mg, 3.45 mmol) was added, and the reaction was stirred at 60 °C for 4 hours. The reaction was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product of the target compound, which was purified by high performance liquid chromatography (Waters-Agilent-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 45-55%, retention time: 5.5-6.8 min, run time: 16 min) to obtain compound 21. 1 H NMR (400 MHz, DMSO-d6): δ 10.72 (s, 1H), 7.25 (d, J = 8.8 Hz, 1H), 7.16 (d, J = 2.4 Hz, 1H), 7.10 (d, J = 2.4 Hz, 1H), 6.80 (dd, J = 8.8, 2.4 Hz, 1H), 4.69 (q, J = 8.8 Hz, 2H), 3.24-3.20 (m, 1H), 3.15-3.08 (m, 1H), 2.91-2.83 (m, 1H), 2.76-2.69 (m, 1H), 2.62-2.56 (m, 1H), 2.11 (s, 3H), 1.94-1.89 (m, 1H), 1.80-1.74 (m, 1H). ESI-MS Theoretical calculation value: [M+H] + = 299.13, found 299.1.

[0305] Example 22

[0306] Synthetic route:

[0307] First step

[0308] Compound 8-2 (2.90 g, 8.75 mmol) was dissolved in 1,2-dichloromethane (40 mL), and trifluoroacetic acid (10 mL) was added to the reaction, which was stirred at 25 °C for 1 hour. After the reaction was completed, it was concentrated under reduced pressure, and the crude product was purified by high performance liquid chromatography (Waters-spherical-C18-20 μm, 100 A, 330 g, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 7-11%, retention time: 15-25 min, run time: 40 min) to obtain compound 22-1. 1H NMR (400 MHz, DMSO-d6): δ 8.44 (s, 1H), 8.15 (d, J = 2.8 Hz, 1H), 7.99 (d, J = 2.8 Hz, 1H), 5.71-5.64 (m, 1H), 4.03-3.96 (m, 1H), 3.88 (s, 3H), 3.80-3.74 (m, 1H), 2.94-2.90 (m, 1H), 2.47-2.42 (m, 1H). ESI-MS Theoretical calculation: [M+H] + = 232.10, found 232.0.

[0309] Second step

[0310] Compound 22-1 (2.20 g, 9.51 mmol) was dissolved in tetrahydrofuran (30 mL), tetrahydroaluminum lithium solution in tetrahydrofuran (38.0 mL, 95.1 mmol, 2.5 mol / L) was added dropwise at 0 °C, the reaction solution was stirred at 60 °C for 12 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, quenched by adding ice water (3.8 mL), 15% sodium hydroxide aqueous solution (3.8 mL) and water (11.4 mL) were added, filtered, the filtrate was concentrated under reduced pressure to obtain the crude product of the target compound, which was purified by high performance liquid chromatography (Waters-spherical-C18-20 μm, 100 A, 220 g, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 11-23%, retention time: 10-26 min, running time: 40 min) to obtain compound 22-2. ESI-MS Theoretical calculation: [M+H] + = 218.12, found 218.1.

[0311] Third step

[0312] Compound 22-2 (200 mg, 0.92 mmol) was dissolved in methanol (5 mL), diisopropyl ethylamine (360 mg, 2.76 mmol) and cyclopropylcarboxaldehyde (190 mg, 2.76 mmol) were added to the reaction solution, the reaction solution was stirred at 25 °C for 0.5 hours, sodium cyanoborohydride (58.0 mg, 0.92 mmol) was added, the reaction solution was stirred at 25 °C for 2 hours. The reaction solution was added to saturated sodium bicarbonate aqueous solution (30 mL), extracted with dichloromethane (30 mL x 3), the organic phase was combined, dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to obtain the crude product of the target compound, which was purified by high performance liquid chromatography (Waters-Agilent-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 25-45%, retention time: 6.5-8.4 min, running time: 16 min) to obtain compound 22. 1H NMR (400 MHz, DMSO-d6): δ 11.15 (s, 1H), 7.92 (d, J = 1.6 Hz, 1H), 7.50 (s, 1H), 7.17 (s, 1H), 3.82 (s, 3H), 3.22-3.18 (m, 2H), 2.96-2.93 (m, 1H), 2.78-2.73 (m, 1H), 2.66-2.63 (m, 1H), 2.31-2.27 (m, 1H), 2.06-2.03 (m, 1H), 1.94-1.86 (m, 1H), 1.83-1.74 (m, 1H), 0.78-0.67 (m, 1H), 0.40-0.36 (m, 2H), 0.05-0.01 (m, 2H). ESI-MS Theoretical Calculation Value: [M+H] + = 272.17, found 272.1.

[0313] Example 23

[0314] Synthetic route:

[0315] First step

[0316] Compound 22-2 (110 mg, 0.51 mmol) was dissolved in tetrahydrofuran (2 mL), diisopropylethylamine (200 mg, 1.53 mmol) and compound 23-1 (120 mg, 0.51 mmol) were added to the reaction solution, and the reaction solution was stirred at 60°C for 16 hours. The reaction solution was added to saturated aqueous sodium bicarbonate solution (5 mL), extracted with dichloromethane (10 mL x 3), the organic phase was combined, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product of the target compound, which was purified by high performance liquid chromatography (Waters-XBridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L aqueous ammonium bicarbonate solution, gradient: 37-55%, retention time: 8.3-8.8 min, run time: 16 min) to obtain compound 23. 1 H NMR (400 MHz, DMSO-d6): δ 11.19 (s, 1H), 7.93 (d, J = 2.4 Hz, 1H), 7.57 (d, J = 2.4 Hz, 1H), 7.19 (d, J = 1.2 Hz, 1H), 3.82 (s, 3H), 3.56-3.50 (m, 1H), 3.40-3.38 (m, 1H), 3.24-3.17 (m, 1H), 3.09-2.88 (m, 3H), 2.80-2.75 (m, 1H), 2.01-1.94 (m, 1H), 1.93-1.85 (m, 1H). ESI-MS Theoretical Calculation Value: [M+H] += 300.12, found 300.0.

[0317] Example 24

[0318] Synthetic route:

[0319] First step

[0320] Compound 22-2 (200 mg, 0.92 mmol) was dissolved in acetonitrile (10 mL), diisopropylethylamine (360 mg, 2.76 mmol) and 2-iodopropane (310 mg, 1.84 mmol) were added to the reaction solution, and the reaction solution was stirred at 70°C for 16 hours. The reaction solution was added to saturated aqueous sodium bicarbonate solution (5 mL), extracted with dichloromethane (10 mL x 3), the organic phase was combined, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product of the target compound, which was purified by high performance liquid chromatography (Waters-XBridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L aqueous ammonium bicarbonate solution, gradient: 17-30%, retention time: 7.5-9.6 min, run time: 17 min) to obtain compound 24. 1 H NMR (400 MHz, DMSO-d6): δ 11.16 (s, 1H), 7.92 (d, J = 2.8 Hz, 1H), 7.48 (d, J = 2.8 Hz, 1H), 7.19 (s, 1H), 3.82 (s, 3H), 3.29-3.26 (m, 1H), 3.22-3.19 (m, 1H), 2.95-2.90 (m, 1H), 2.82-2.78 (m, 1H), 2.67-2.61 (m, 1H), 2.41-2.35 (m, 1H), 1.84-1.79 (m, 1H), 1.71-1.65 (m, 1H), 1.01 (d, J = 6.4 Hz, 3H), 0.84 (d, J = 6.4 Hz, 3H). ESI-MS Theoretical calculation: [M+H] + = 260.17, found 260.1.

[0321] Example 25

[0322] Synthetic route:

[0323] First step

[0324] Compound 22-2 (200 mg, 0.92 mmol) was dissolved in methanol (5 mL), triethylamine (280 mg, 2.76 mmol) and acetaldehyde (405 mg, 4.60 mmol) were added into the reaction solution, the reaction solution was stirred at 25 °C for 0.5 h, sodium cyanoborohydride (58.0 mg, 0.92 mmol) was added, the reaction solution was stirred at 25 °C for 2 h. The reaction solution was added into saturated aqueous sodium bicarbonate solution (30 mL), extracted with dichloromethane (30 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to obtain the crude product of the target compound, which was purified by high performance liquid chromatography (Waters-Agilent-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L aqueous ammonium bicarbonate solution, gradient: 15-35%, retention time: 6.6-8.3 min, run time: 16 min) to obtain compound 25. 1 H NMR (400 MHz, DMSO-d6): δ 11.16 (s, 1H), 7.92 (d, J = 2.8 Hz, 1H), 7.51 (d, J = 2.8 Hz, 1H), 7.18 (d, J = 2.0 Hz, 1H), 3.82 (s, 3H), 3.25-3.17 (m, 2H), 2.91-2.87 (m, 1H), 2.78-2.74 (m, 1H), 2.56-2.53 (m, 1H), 2.48-2.45 (m, 1H), 2.19-2.14 (m, 1H), 1.93-1.89 (m, 1H), 1.84-1.75 (m, 1H), 0.85 (t, J = 7.2 Hz, 3H). ESI-MS Theoretical calculation: [M+H] + = 246.15, found 246.0.

[0325] Example 26

[0326] Synthetic route:

[0327] First step

[0328] Compound 8-2 (142 mg, 0.45 mmol) was dissolved in tetrahydrofuran (6 mL), deuterium tetrahydroaluminum lithium (189 mg, 4.50 mmol) was slowly added at 0 °C, the reaction solution was stirred at 60 °C for 1 hour under nitrogen atmosphere. The reaction solution was cooled to room temperature, ice water (0.05 mL) was added to quench, 15% sodium hydroxide aqueous solution (0.05 mL) and water (0.1 mL) were added, filtered, the filtrate was concentrated under reduced pressure to obtain the crude product of the target compound, purified by high performance liquid chromatography (Waters-Agilent-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 10-30%, retention time: 7.8-9.8 min, running time: 16 min) to obtain compound 26. 1 H NMR (400 MHz, DMSO-d6): δ 11.16 (s, 1H), 7.92 (d, J = 2.8 Hz, 1H), 7.50 (d, J = 2.8 Hz, 1H), 7.18 (d, J = 2.0 Hz, 1H), 3.82 (s, 3H), 3.22 - 3.19 (m, 1H), 3.13-3.07 (m, 1H), 2.87-2.82 (m, 1H), 2.75-2.69 (m, 1H), 2.63-2.58 (m, 1H), 1.94-1.88 (m, 1H), 1.82-1.76 (m, 1H). ESI-MS Theoretical calculation value: [M+H] + = 235.16, found 235.1.

[0329] Example 27

[0330] Synthetic route:

[0331] First step

[0332] Compound 22-2 (100 mg, 0.46 mmol) was dissolved in ethanol (3 mL), diisopropylethylamine (178 mg, 1.38 mmol) and compound 27-1 (146 mg, 1.38 mmol) were added to the reaction solution, the reaction solution was stirred at 60 °C for 2 hours. The reaction solution was added to saturated sodium bicarbonate aqueous solution (5 mL), extracted with dichloromethane (10 mL x 3), the organic phase was combined, dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to obtain the crude product of the target compound, purified by high performance liquid chromatography (Waters-XBridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 23-33%, retention time: 6.5-7.3 min, running time: 16 min) to obtain compound 27. 1H NMR (400 MHz, DMSO-d6): δ 11.18 (s, 1H), 7.92 (d, J = 2.8 Hz, 1H), 7.53 (d, J = 2.8 Hz, 1H), 7.21 (d, J = 2.4 Hz, 1H), 3.82 (s, 3H), 3.32-3.29 (m, 2H), 3.14-3.02 (m, 2H), 3.01 (s, 3H), 2.94-2.87 (m, 2H), 2.77-2.66 (m, 2H), 2.57-2.53 (m, 1H), 1.97-1.90 (m, 1H), 1.82-1.74 (m, 1H). ESI-MS Theoretical Calculation: [M+H] + = 324.13 Found 324.1.

[0333] Example 28

[0334] Synthetic route:

[0335] First step

[0336] Compound (2S)-1,1,1-trifluoropropan-2-ol (7.41 g, 65.0 mmol) was dissolved in N,N-dimethylformamide (130 mL), sodium hydride (2.84 g, 70.9 mmol, 60% purity) was added slowly at 0 °C under nitrogen atmosphere, stirred at 0 °C for 0.5 h, compound 28-1 (13.0 g, 59.1 mmol) was added slowly, stirred at 25 °C for 0.5 h. The reaction solution was added to saturated aqueous ammonium chloride solution (200 mL), extracted with ethyl acetate (200 mL x 3), the combined organic phase was washed with saturated brine (200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 15 / 1, v / v) to give compound 28-2. 1 H NMR (400 MHz, DMSO-d6): δ 8.08 (dd, J = 8.8, 1.2 Hz, 1H), 7.68 (t, J = 2.8 Hz, 1H), 7.32 (dd, J = 8.8, 2.8 Hz, 1H), 5.58-5.51 (m, 1H), 1.45 (d, J = 6.4 Hz, 3H).

[0337] Second step

[0338] Compound 28-2 (7.80 g, 24.8 mmol) was dissolved in ethanol (66 mL) and water (13 mL), iron powder (6.94 g, 124 mmol), ammonium chloride (6.64 g, 124 mmol) were added, and stirred at 80 °C for 2 h. The reaction solution was cooled to room temperature, filtered, water (150 mL) was added to the filtrate, and ethyl acetate (150 mL x 3) was added to extract, and the organic phases were combined and washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 15 / 1, v / v) to obtain compound 28-3. 1 H NMR (400 MHz, DMSO-d6): δ 7.14 (d, J = 2.8 Hz, 1H), 6.85 (dd, J = 8.8, 2.8 Hz, 1H), 6.75 (d, J = 8.8 Hz, 1H), 5.01 (s, 2H), 4.97-4.90 (m, 1H), 1.34 (d, J = 6.4 Hz, 3H).

[0339] Third step

[0340] Compound 28-3 (5.76 g, 20.3 mmol) was dissolved in triethylamine (50 mL), trimethylsilylethynyl (3.98 g, 40.6 mmol), dichlorobispalladium (712 mg, 1.01 mmol) and cuprous iodide (193 mg, 1.01 mmol) were added under nitrogen atmosphere, and stirred at 50 °C for 16 h. The reaction solution was cooled to room temperature, filtered, water (50 mL) was added to the filtrate, and ethyl acetate (50 mL x 3) was added to extract, and the organic phases were combined and washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 20 / 1, v / v) to obtain compound 28-4. ESI-MS Theoretical calculation: [M+H] = 302.11 Found 302.0. +

[0341] Fourth step

[0342] Compound 28-4 (1.80 g, 5.97 mmol) was dissolved in N,N-dimethylformamide (27 mL), cuprous iodide (2.27 g, 11.9 mmol) was added under nitrogen atmosphere, and stirred at 100 °C for 2 h. The reaction solution was cooled to room temperature, water (30 mL) was added, and ethyl acetate (100 mL x 3) was added to extract, and the organic phases were combined and washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 15 / 1, v / v) to obtain compound 28-5. 1 ​H NMR (400 MHz, DMSO-d6): δ 11.02 (s, 1H), 7.35-7.30 (m, 2H), 7.22 (d, J = 2.4 Hz, 1H), 6.82 (dd, J = 8.8, 2.4 Hz, 1H), 6.34 (dd, J = 7.2, 5.2 Hz, 1H), 5.04-4.97 (m, 1H), 1.40 (d, J = 6.4 Hz, 3H). ESI-MS Theoretical calculation value: [M+H] + = 230.07, found 230.0.

[0343] Fifth step

[0344] (R)-N-carboxylic acid tert-butyl ester-azetidine-2-carboxylic acid (1.32 g, 6.55 mmol) was dissolved in dichloromethane (20 mL), oxalyl chloride (0.675 mL, 7.85 mmol) was added dropwise at 0 °C, the reaction solution was stirred at 0 °C for 10 min, N,N-dimethylformamide (48.0 mg, 0.695 mmol) was added slowly, the reaction solution was stirred at 25 °C for 1 h. The reaction solution was concentrated under reduced pressure to obtain the crude intermediate state. Compound 28-5 (1.50 g, 6.54 mmol) was dissolved in dichloromethane (15 mL), ethyl magnesium bromide (3.44 mL, 6.87 mmol, 2 mol / L) was added dropwise slowly at 0 °C under nitrogen atmosphere, and the reaction solution was stirred at 0 °C for 0.5 h. The crude intermediate state was dissolved in dichloromethane (20 mL), and was added dropwise to the reaction solution at 0 °C, and the reaction solution was stirred at 0 °C for 0.5 h. The reaction solution was added to saturated aqueous citric acid solution (50 mL), extracted with dichloromethane (50 mL x 3), and the combined organic phase was washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / ethyl acetate, 1 / 1, v / v) to obtain compound 28-6. ESI-MS Theoretical calculation value: [M+H] + = 413.16, found 413.0.

[0345] Sixth step

[0346] Compound 28-6 (200 mg, 0.48 mmol) was dissolved in tetrahydrofuran (5 mL), tetrahydroaluminum lithium solution (1.92 mL, 4.80 mmol, 2.5 mol / L) was added dropwise at 0 ℃, the reaction solution was stirred at 60 ℃ for 8 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, quenched by adding ice water (0.19 mL), 15% sodium hydroxide aqueous solution (0.19 mL) and water (0.57 mL) were added, filtered, the filtrate was concentrated under reduced pressure to obtain the crude product of the target compound, which was purified by high performance liquid chromatography (Waters-XBridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 40-60%, retention time: 6.6-8.3 min, running time: 17 min) to obtain compound 28. 1 H NMR (400 MHz, DMSO-d6): δ 10.72 (s, 1H), 7.24 (d, J = 8.8 Hz, 1H), 7.19 (d, J = 2.4 Hz, 1H), 7.10 (d, J = 2.4 Hz, 1H), 6.80 (dd, J = 8.8, 2.4 Hz, 1H), 5.09-4.98 (m, 1H), 3.24-3.19 (m, 1H), 3.12-3.06 (m, 1H), 2.90-2.82 (m, 1H), 2.76-2.69 (m, 1H), 2.62-2.57 (m, 1H), 2.11 (s, 3H), 1.96-1.89 (m, 1H), 1.82-1.74 (m, 1H), 1.41 (d, J = 6.4 Hz, 3H). ESI-MS Theoretical calculation value: [M+H] + = 313.14, found 313.0.

[0347] Example 29

[0348] Synthetic route:

[0349] First step

[0350] Compound 8-2 (1.00 g, 3.15 mmol) was dissolved in N,N-dimethylformamide (20 mL), and sodium hydride (151 mg, 3.78 mmol, 60% purity) was slowly added at 0°C under a nitrogen atmosphere. The mixture was stirred at 0°C for 0.5 h, and p-toluenesulfonyl chloride (721 mg, 3.78 mmol) was added. The mixture was stirred at 25°C for 3 h. The reaction solution was added to saturated aqueous ammonium chloride solution (20 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine solution (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1, v / v) to obtain compound 29-1. ESI-MS Theoretical value: [M+H]=472.18, Found: 472.0. +

[0351] Second step

[0352] Compound 29-1 (100 mg, 0.91 mmol) was dissolved in anhydrous dichloromethane (10 mL), and trifluoroacetic acid (4 mL) was added. The mixture was stirred at 25°C for 1 h. The reaction solution was concentrated under reduced pressure, and saturated aqueous sodium bicarbonate solution (20 mL) was added to the residue. The mixture was extracted with dichloromethane (50 mL x 3), and the combined organic phases were washed with saturated brine solution (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 29-2. ESI-MS Theoretical value: [M+H]=372.13, Found: 372.1. +

[0353] Third step

[0354] Compound 29-2 (200 mg, 0.27 mmol) was dissolved in N,N-dimethylformamide (4 mL), and bromoethanol (169 mg, 1.35 mmol) and potassium carbonate (112 mg, 0.81 mmol) were added to the reaction solution. The mixture was stirred at 70°C for 6 h. The reaction solution was added to saturated aqueous ammonium chloride solution (30 mL), and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol, 10 / 1, v / v) to obtain compound 29-3. ESI-MS Theoretical value: [M+H]=416.16, Found: 416.5. +

[0355] Fourth step

[0356] ​​​Compound 29-3 (55.0 mg, 0.13 mmol) was dissolved in anhydrous ethanol (3 mL) and water (1 mL), sodium hydroxide (26.0 mg, 0.65 mmol) was added, and the reaction solution was stirred at 70 °C for 6 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product of the target compound, which was purified by high performance liquid chromatography (Waters-XBridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 28-38%, retention time: 9.5-10.5 min, run time: 17 min) to obtain compound 29. 1 H NMR (400 MHz, DMSO-d6): δ 11.16 (s, 1H), 7.92 (d, J = 2.4 Hz, 1H), 7.52 (d, J = 2.4 Hz, 1H), 7.18 (d, J = 2.0 Hz, 1H), 4.42-4.36 (m, 1H), 3.82 (s, 3H), 3.38-3.35 (m, 2H), 3.30-3.27 (m, 2H), 2.96-2.91 (m, 1H), 2.79-2.73 (m, 2H), 2.57-2.54 (m, 1H), 2.35-2.30 (m, 1H), 1.95-1.90 (m, 1H), 1.84-1.78 (m, 1H). ESI-MS Theoretical calculation value: [M+H] + = 262.15, found 262.1.

[0357] Example 30

[0358] Synthetic route:

[0359] First step

[0360] Compound 29-2 (180 mg, 0.48 mmol) was dissolved in 1,2-dichloroethane (15 mL), and compound 30-1 (167 mg, 0.96 mmol) and sodium triacetylborohydride (203 mg, 0.96 mmol) were added to the reaction solution, which was stirred at 60 °C for 16 hours. Saturated sodium bicarbonate aqueous solution (30 mL) was added to the reaction solution, which was extracted with dichloromethane (30 mL x 3), and the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1, v / v) to obtain compound 30-2. ESI-MS Theoretical calculation value: [M+H] + = 412.16, found 412.5.

[0361] Second step

[0362] Compound 30-2 (65.0 mg, 0.16 mmol) was dissolved in anhydrous ethanol (3 mL) and water (1.2 mL), lithium hydroxide monohydrate (67.1 mg, 1.60 mmol) was added, and the reaction was stirred at 60 °C for 4 h. The reaction was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product of the target compound, which was purified by high performance liquid chromatography (Waters-XBridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 28-38%, retention time: 9.5-10.5 min, run time: 17 min) to obtain compound 30. 1 H NMR (400 MHz, DMSO-d6): δ 11.16 (s, 1H), 7.92 (d, J = 2.8 Hz, 1H), 7.48 (d, J = 2.8 Hz, 1H), 7.18 (s, 1H), 3.82 (s, 3H), 3.55-3.49 (m, 1H), 3.20-3.16 (m, 1H), 2.96-2.85 (m, 2H), 2.75-2.68 (m, 1H), 1.92-1.85 (m, 1H), 1.84-1.79 (m, 1H), 1.76-1.68 (m, 1H), 0.34-0.23 (m, 3H), 0.15-0.11 (m, 1H). ESI-MS Theoretical calculation: [M+H] + = 258.15, found 258.1.

[0363] Example 31

[0364] Synthetic route:

[0365] First step

[0366] Compound 22-2 (200 mg, 0.92 mmol) was dissolved in ethylene glycol dimethyl ether (5 mL), triethylamine (189 mg, 1.87 mmol) and methyl epoxide (265 mg, 3.68 mmol) were added to the reaction, and the reaction was stirred at 70 °C for 16 h. The reaction was concentrated under reduced pressure to obtain the crude product of the target compound, which was purified by high performance liquid chromatography (Waters-XBridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 18-28%, retention time: 9.3-11.3 min, run time: 17 min) to obtain compound 31. 1H NMR (400 MHz, DMSO-d6): δ 11.15 (s, 1H), 7.91 (d, J = 2.8 Hz, 1H), 7.50 (d, J = 2.8 Hz, 1H), 7.17 (d, J = 2.4 Hz, 1H), 3.98-2.94 (m, 1H), 3.82 (s, 3H), 3.39-3.37 (m, 1H), 3.34-3.30 (m, 1H), 2.92-2.87 (m, 1H), 2.75-2.69 (m, 2H), 2.34 (d, J = 12.4 Hz, 1H), 2.18 (d, J = 12.4 Hz, 1H), 1.95-1.88 (m, 1H), 1.85-1.77 (m, 1H), 1.02 (s, 3H), 1.01 (s, 3H). ESI-MS Theoretical mass: [M+H] + = 290.18 Found 290.1.

[0367] Example 32

[0368] Synthetic route:

[0369] First step

[0370] Compound (2R)-1,1,1-trifluoropropan-2-ol (9.70 g, 85.0 mmol) was dissolved in N,N-dimethylformamide (200 mL), sodium hydride (2.23 g, 92.7 mmol, 60% purity) was slowly added at 0 °C under nitrogen atmosphere, stirred at 0 °C for 0.5 h, compound 28-1 (17.0 g, 77.3 mmol) was slowly added, stirred at 25 °C for 0.5 h. The reaction solution was added to saturated aqueous ammonium chloride solution (200 mL), extracted with ethyl acetate (200 mL x 3), the organic phase was combined and washed with saturated brine (200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 15 / 1, v / v) to obtain compound 32-1. 1 H NMR (400 MHz, DMSO-d6): δ 8.09 (d, J = 8.0 Hz, 1H), 7.69-7.68 (d, J = 2.8 Hz, 1H), 7.36-7.30 (m, 1H), 5.59-5.53 (m, 1H), 1.45 (d, J = 6.4 Hz, 3H).

[0371] Second step

[0372] Compound 32-1 (22.0 g, 70.1 mmol) was dissolved in ethanol (500 mL) and water (100 mL), iron powder (19.6 g, 350 mmol), ammonium chloride (18.7 g, 350 mmol) were added, and stirred at 80 °C for 6 h. The reaction was cooled to room temperature, filtered, the filtrate was added to water (150 mL), extracted with ethyl acetate (150 mL x 3), the organic phases were combined, washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 15 / 1, v / v) to obtain compound 32-2. 1 H NMR (400 MHz, DMSO-d6): δ 7.15 (d, J = 2.8 Hz, 1H), 6.86 (dd, J = 8.0, 2.8 Hz, 1H), 6.76 (d, J = 8.0 Hz, 1H), 5.02 (s, 2H), 4.96-4.91 (m, 1H), 1.35 (d, J = 6.4 Hz, 3H).

[0373] Third step

[0374] Compound 32-2 (19.0 g, 60.5 mmol) was dissolved in triethylamine (150 mL), trimethylsilylethynyl (11.9 g, 121 mmol), dichlorobispalladium (2.12 g, 3.03 mmol) and cuprous iodide (580 mg, 3.03 mmol) were added under nitrogen atmosphere, and stirred at 50 °C for 16 h. The reaction was cooled to room temperature, filtered, the filtrate was added to water (100 mL), extracted with ethyl acetate (150 mL x 3), the organic phases were combined, washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 20 / 1, v / v) to obtain compound 32-3. 1 H NMR (400 MHz, DMSO-d6): δ 6.90 (d, J = 2.8 Hz, 1H), 6.84 (dd, J = 8.8, 2.8 Hz, 1H), 6.67 (d, J = 8.8 Hz, 1H), 5.07 (s, 2H), 4.95-4.86 (m, 1H), 1.33 (d, J = 6.4 Hz, 3H), 0.23 (s, 9H).

[0375] Fourth step

[0376] Compound 32-3 (8.90 g, 29.5 mmol) was dissolved in N,N-dimethylformamide (90 mL), and cuprous iodide (11.3 g, 59.1 mmol) was added under a nitrogen atmosphere. The reaction was stirred at 100 °C for 2 h. The reaction was cooled to room temperature, water (100 mL) was added, and the mixture was extracted with ethyl acetate (200 mL x 3). The organic phase was combined and washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 15 / 1, v / v) to give compound 32-4. 1 H NMR (400 MHz, DMSO-d6): δ 11.01 (s, 1H), 7.35-7.29 (m, 2H), 7.22 (d, J = 2.8 Hz, 1H), 6.82 (dd, J = 8.8, 2.8 Hz, 1H), 6.35 (t, J = 2.0 Hz, 1H), 5.05-4.96 (m, 1H), 1.40 (d, J = 6.4 Hz, 3H). ESI-MS Theoretical calculation: [M+H] + = 230.07 Found 230.0.

[0377] Fifth step

[0378] (R)-tert-butyl N-carboxylate-azetidine-2-carboxylate (1.98 g, 9.83 mmol) was dissolved in dichloromethane (30 mL), and oxalyl chloride (0.683 mL, 11.8 mmol) was added dropwise at 0 °C. The reaction was stirred at 0 °C for 10 min, and N,N-dimethylformamide (72.0 mg, 1.04 mmol) was added slowly. The reaction was stirred at 25 °C for 1 h. The reaction was concentrated under reduced pressure to give a crude intermediate. Compound 32-4 (2.00 g, 8.73 mmol) was dissolved in dichloromethane (15 mL), and ethyl magnesium bromide (3.44 mL, 6.87 mmol, 2 mol / L) was added dropwise slowly at 0 °C under a nitrogen atmosphere. The reaction was stirred at 0 °C for 0.5 h. The crude intermediate was dissolved in dichloromethane (20 mL) and added dropwise to the reaction at 0 °C. The reaction was stirred at 0 °C for 0.5 h. The reaction was added to saturated aqueous citric acid (50 mL), and the mixture was extracted with dichloromethane (50 mL x 3). The organic phase was combined and washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / ethyl acetate, 1 / 1, v / v) to give compound 32-5. ESI-MS Theoretical calculation: [M+H] + = 413.16, Found 413.0.

[0379] Sixth step

[0380] Compound 32-5 (144 mg, 0.35 mmol) was dissolved in tetrahydrofuran (7 mL), and a tetrahydro-lithium aluminum solution in tetrahydrofuran (1.40 mL, 3.50 mmol, 2.5 mol / L) was added dropwise at 0 °C. The reaction solution was stirred at 60 °C for 8 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, quenched by adding ice water (0.14 mL), and then 15% sodium hydroxide aqueous solution (0.14 mL) and water (0.42 mL) were added. Filtration and concentration under reduced pressure gave a crude product containing the target compound, which was purified by high performance liquid chromatography (Waters-XBridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 38-51%, retention time: 7.7-9.5 min, run time: 16 min) to give compound 32. 1 H NMR (400 MHz, DMSO-d6): δ 10.72 (s, 1H), 7.24 (d, J = 8.8 Hz, 1H), 7.19 (d, J = 2.4 Hz, 1H), 7.10 (d, J = 2.4 Hz, 1H), 6.80 (dd, J = 8.8, 2.4 Hz, 1H), 5.07-5.00 (m, 1H), 3.26-3.22 (m, 1H), 3.13-3.07 (m, 1H), 2.86-2.82 (m, 1H), 2.75-2.67 (m, 1H), 2.63-2.58 (m, 1H), 2.11 (s, 3H), 1.97-1.90 (m, 1H), 1.82-1.73 (m, 1H), 1.41 (d, J = 6.4 Hz, 3H). ESI-MS Theoretical calculation: [M+H] + = 313.14, found 313.0.

[0381] Example 33

[0382] Synthetic route:

[0383] First step

[0384] Compound 33-1 (8.86 g, 29.0 mmol) was dissolved in N,N-dimethylformamide (125 mL), and liquid bromine (1.63 mL, 31.9 mmol) was slowly added at 0 °C under a nitrogen atmosphere. The reaction solution was stirred at 25 °C for 1 hour. The reaction solution was added to a sodium bicarbonate aqueous solution (140 mL), and extracted with ethyl acetate (300 mL x 3). The combined organic phase was washed with saturated brine (300 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1, v / v) to give compound 33-2. 1H NMR (400 MHz, CDC13): δ 7.84 (d, J = 8.8 Hz, 1H), 7.68 (d, J = 8.8 Hz, 2H), 7.55 (s, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.25 (dd, J = 8.8, 2.4 Hz, 1H), 7.18 (d, J = 7.6 Hz, 2H), 2.29 (s, 3H).

[0385] Second step

[0386] In a nitrogen-filled glove box, compound 33-2 (500 mg, 1.30 mmol), (2R)-2- (bromomethyl)azetidine-1-carboxylate (490 mg, 1.95 mmol), anhydrous sodium carbonate (276 mg, 2.60 mmol), tris(trimethylsilyl)silane (480 mg, 1.95 mmol), nickel dichloride dimethyl oxide (14.0 mg, 0.065 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (17.5 mg, 0.065 mmol) and bis[2-(2,4-difluorophenyl)-5- trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium dimethyl phosphate (15.0 mg, 0.013 mmol) were dissolved in N,N-dimethylacetamide (8 mL). The reaction was placed under 34 W blue LED (420 nm) irradiation and stirred at 25 °C for 16 h. After the reaction was completed, the blue light was turned off, the reaction was added to water (50 mL), extracted with dichloromethane (50 mL x 3), the organic phases were combined and washed with saturated brine (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 1, v / v) to obtain compound 33-3. 1 H NMR (400 MHz, DMSO-d6): δ 7.91 (d, J = 8.8 Hz, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.70 (s, 1H), 7.61 (d, J = 2.4 Hz, 1H), 7.39-7.34 (m, 3H), 4.43-4.38 (m, 1H), 3.65-3.61 (m, 1H), 3.34-3.30 (m, 2H), 3.01-2.98 (m, 1H), 2.31 (s, 3H), 2.17-2.10 (m, 1H), 1.83-1.77 (m, 1H), 1.34 (s, 9H). ESI-MS theoretical value: [M+Na] + = 497.14, found 497.1.

[0387] Third step

[0388] Compound 33-3 (335 mg, 0.71 mmol) was dissolved in 1,4-dioxane (10 mL) and water (2 mL), and cyclopropylboronic acid (91.5 mg, 1.06 mmol), potassium phosphate (452 mg, 2.13 mmol) and methane sulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'- biphenyl) (2'-amino-1,1'-biphenyl-2-yl)palladium(II) (60.1 mg, 0.071 mmol) were added. The reaction was stirred at 100 °C for 16 h under nitrogen atmosphere. The reaction was cooled to room temperature, water (30 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phase was combined and washed with saturated brine (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1, v / v) to give compound 33-4. ESI-MS calculated value: [M+H-56] + = 425.21, found 425.1.

[0389] Fourth Step

[0390] Compound 33-4 (270 mg, 0.56 mmol) was dissolved in anhydrous dichloromethane (10 mL), and trifluoroacetic acid (2 mL) was added. The reaction was stirred at 25 °C for 1 h. The reaction was concentrated under reduced pressure, and saturated aqueous sodium bicarbonate solution (20 mL) was added to the residue. The mixture was extracted with dichloromethane (50 mL x 3), and the organic phase was combined and washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 33-5. ESI-MS calculated value: [M+H] + = 381.16, found 381.1.

[0391] Fifth Step

[0392] Compound 33-5 (210 mg, 0.55 mmol) was dissolved in 1,2-dichloroethane (5 mL), and triethylamine (167 mg, 1.65 mmol) and 37% formaldehyde solution (134 mg, 165 mmol) were added to the reaction. The reaction was stirred at 25 °C for 0.5 h, and sodium triacetylboration hydride (233 mg, 1.10 mmol) was added. The reaction was stirred at 25 °C for 2 h. The reaction was added to saturated aqueous sodium bicarbonate solution (30 mL), and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phase was combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under vacuum. The crude product was purified by silica gel column chromatography (dichloromethane / methanol, 15 / 1, v / v) to give compound 33-6. ESI-MS calculated value: [M+H] + = 395.17, found 395.2.

[0393] Sixth step

[0394] Compound 33-6 (125 mg, 0.32 mmol) was dissolved in anhydrous methanol (3 mL) and water (1 mL), potassium hydroxide (180 mg, 3.20 mmol) was added, and the reaction was stirred at 80 °C for 2 hours. The reaction was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product of the target compound, which was purified by high performance liquid chromatography (Waters-XBridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 33-50%, retention time: 8.0-10.3 min, run time: 18 min) to obtain compound 33. 1 H NMR (400 MHz, DMSO-d6): δ 10.61 (s, 1H), 7.22 (s, 1H), 7.18 (d, J = 8.4 Hz, 1H), 7.03 (d, J = 2.0 Hz, 1H), 6.77 (dd, J = 8.4, 2.0 Hz, 1H), 3.32-3.30 (m, 1H), 3.25-3.17 (m, 1H), 3.10-3.03 (m, 1H), 2.74-2.69 (m, 1H), 2.62-2.57 (m, 1H), 2.11 (s, 3H), 1.99-1.95 (m, 1H), 1.92-1.87 (m, 1H), 1.82-1.72 (m, 1H), 0.93-0.85 (m, 2H), 0.66-0.58 (m, 2H). ESI-MS Theoretical calculation: [M+H] + = 241.16, found 241.1.

[0395] Example 34

[0396] Synthetic route:

[0397] First step

[0398] Compound 14-3 (1.68 g, 4.02 mmol) was dissolved in tetrahydrofuran (10 mL), ethanol (10 mL) and water (4 mL), and lithium hydroxide monohydrate (843 mg, 20.1 mmol) was added to the reaction system, which was stirred at 25 °C for 2 hours. Water (40 mL) was added to the reaction, and ethyl acetate (100 mL x 3) was extracted, and the organic phase was combined and washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 1, v / v) to obtain compound 34-1. 1H NMR (400 MHz, DMSO-d6): δ 12.61 (s, 1H), 7.37 (d, J = 8.8 Hz, 1H), 7.09 (s, 1H), 6.98 (dd, J = 8.8, 2.4 Hz, 1H), 4.51-4.47 (m, 1H), 3.78 (s, 3H), 3.72-3.66 (m, 1H), 3.65-3.57 (m, 1H), 3.38-3.31 (m, 1H), 3.21-3.18 (m, 1H), 2.18-2.12 (m, 1H), 1.99-1.94 (m, 1H), 1.38 (s, 9H). ESI-MS Theoretical calculation value: [M+H] + = 318.17, found 318.1.

[0399] Second step

[0400] Compound 34-1 (945 mg, 2.98 mmol) was dissolved in N,N-dimethylformamide (10 mL), sodium hydride (143 mg, 3.58 mmol, 60% purity) was slowly added at 0 °C under nitrogen atmosphere, and stirred at 0 °C for 0.5 h. p-Toluenesulfonyl chloride (682 mg, 3.58 mmol) was added, and stirred at 25 °C for 2 h. The reaction solution was added to an aqueous ammonium chloride solution (50 mL), extracted with ethyl acetate (50 mL x 3), and the combined organic phases were washed with saturated brine (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1, v / v) to obtain compound 34-2. ESI-MS Theoretical calculation value: [M+H] + = 472.18, found 472.1.

[0401] Third step

[0402] Compound 34-2 (1.20 g, 2.54 mmol) was dissolved in 1,2-dichloromethane (10 mL), and trifluoroacetic acid (5 mL, 67.3 mmol) was slowly added at 0 °C. The mixture was stirred at 25 °C for 2 h. The reaction solution was added to a saturated aqueous sodium bicarbonate solution (100 mL), extracted with dichloromethane (100 mL x 3), and the combined organic phases were washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 34-3. ESI-MS Theoretical calculation value: [M+H] + = 372.13, found 372.1.

[0403] Fourth step

[0404] Compound 34-3 (300 mg, 0.81 mmol) was dissolved in methanol (5 mL), N, N- diisopropylethylamine (310 mg, 2.43 mmol) and acetaldehyde (143 mg, 1.62 mmol) were added, and stirred at 25 °C for 0.5 h. Sodium cyanoborohydride (51.4 mg, 0.82 mmol) was added, and stirred at 25 °C for 2 h. The reaction solution was added to saturated aqueous sodium bicarbonate solution (50 mL), and extracted with ethyl acetate (50 mL x 3), and the combined organic phase was washed with saturated brine (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol, 20 / 1, v / v) to obtain compound 34-4. ESI-MS theoretical calculation: [M+H] = 400.16, found 400.0. +

[0405] Fifth step

[0406] Compound 34-4 (170 mg, 0.43 mol) was dissolved in tetrahydrofuran (2 mL), methanol (2 mL) and water (0.8 mL), and lithium hydroxide monohydrate (90.2 mg, 2.15 mmol) was added. The reaction solution was stirred at 25 °C for 12 h. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product of the target compound. Purification by high performance liquid chromatography (Waters-XBridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 28-48%, retention time: 7.5-9.5 min, run time: 17 min) to obtain compound 34. 1 H NMR (400 MHz, DMSO-d6): δ 12.49 (s, 1H), 7.34 (d, J = 8.8 Hz, 1H), 7.14 (d, J = 2.0 Hz, 1H), 6.95 (dd, J = 8.8, 2.0 Hz, 1H), 3.78 (s, 3H), 3.30-3.24 (m, 2H), 3.12-3.07 (m, 1H), 3.00-2.94 (m, 1H), 2.58-2.53 (m, 1H), 2.49-2.46 (m, 1H), 2.19-2.13 (m, 1H), 1.93-1.81 (m, 2H), 0.84 (t, J = 7.2 Hz, 3H). ESI-MS theoretical calculation: [M+H] = 246.15, found 246.1. +

[0407] Example 35

[0408] Synthetic route:

[0409] First step ​​

[0410] Compound 19-4 (250 mg, 0.53 mmol) was dissolved in 1,2-dichloromethane (10 mL), trifluoroacetic acid (3.5 mL, 47.1 mmol) was added slowly at 0 °C, and the reaction was stirred at 25 °C for 2 h. The reaction was added to saturated aqueous sodium bicarbonate solution (50 mL), extracted with dichloromethane (50 mL x 3), and the combined organic phases were washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 35-1. ESI-MS calculated for [M+H] = 372.13, found 372.4. +

[0411] Second step

[0412] Compound 35-1 (216 mg, 0.58 mmol) was dissolved in N,N-dimethylformamide (3.5 mL), potassium carbonate (240 mg, 1.74 mmol), potassium iodide (9.6 mg, 0.058 mmol), and 2-bromoethanol (217 mg, 1.74 mmol) were added, and the reaction was stirred at 70 °C for 2 h. The reaction was added to water (20 mL), extracted with ethyl acetate (20 mL x 3), and the combined organic phases were washed with saturated brine (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol, 10 / 1, v / v) to give compound 35-2. ESI-MS calculated for [M+H] = 416.16, found 416.4. +

[0413] Third step

[0414] Compound 35-2 (185 mg, 0.45 mol) was dissolved in ethanol (2 mL) and water (0.5 mL), sodium hydroxide (54.0 mg, 1.35 mmol) was added, and the reaction was stirred at 60 °C for 4 h. The reaction was filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by high performance liquid chromatography (Waters-XBridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-0.04% ammonia water+7.5 mmol / L ammonium bicarbonate aqueous solution, gradient: 20-25%, retention time: 6.2-8.0 min, run time: 16 min) to give compound 35. 1 ​​¹H NMR (400MHz, DMSO-d⁶): δ 10.81 (s, 1H), 7.61 (d, J = 8.8Hz, 1H), 7.25 (s, 1H), 6.49 (d, J = 8.8Hz, 1H), 4.33–4.29 (m, 1H), 3.86 (s, 3H), 3.41–3.36 (m, 2H), 3.29–3.25 (m, 2H), 2.95–2.89 (m, 1H), 2.79–2.75 (m, 1H), 2.70–2.65 (m, 1H), 2.60–2.55 (m, 1H), 2.35–2.29 (m, 1H), 1.92–1.81 (m, 2H). ESI-MS theoretical calculation: [M+H] + =262.15, measured value 262.0.

[0415] Example 36

[0416] Synthesis route:

[0417] first step

[0418] Compound 34-3 (250 mg, 0.67 mmol) was dissolved in N,N-dimethylformamide (5 mL), and potassium carbonate (278 mg, 2.01 mmol) and 2-bromoethanol (251 mg, 2.01 mmol) were added. The mixture was stirred at 25 °C for 3 hours. The reaction solution was extracted with water (20 mL) and ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane / methanol, 10 / 1, v / v) to give compound 36-1. ESI-MS theoretical calculation: [M+H] + =416.16, measured value 416.5.

[0419] Step 2

[0420] Compound 36-1 (110 mg, 0.26 mol) was dissolved in tetrahydrofuran (1 mL), methanol (1 mL), and water (1 mL). Lithium hydroxide monohydrate (54.6 mg, 1.37 mmol) was added, and the reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product containing the target compound. Compound 36-1 was purified by high performance liquid chromatography (Waters-XBridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 17-27%, retention time: 7.8-8.7 min, run time: 17 min) to obtain compound 36-1. 1¹H NMR (400MHz, DMSO-d⁶): δ 12.51 (s, 1H), 7.35 (d, J = 8.8Hz, 1H), 7.15 (s, 1H), 6.96 (d, J = 8.8Hz, 1H), 4.44–4.39 (m, 1H), 3.79 (s, 3H), 3.48–3.43 (m, 1H), 3.39–3.35 (m, 2H), 3.17–3.09 (m, 1H), 2.92–2.88 (m, 1H), 2.85–2.70 (m, 1H), 2.63–2.52 (m, 2H), 2.40–2.29 (m, 1H), 1.98–1.85 (m, 2H). ESI-MS theoretical calculation: [M+H] + =262.15, measured value 262.0.

[0421] Example 37

[0422] Synthesis route:

[0423] first step

[0424] Compound 3-2 (2.12 g, 6.66 mmol) was dissolved in 1,2-dichloromethane (40 mL), and trifluoroacetic acid (10 mL) was slowly added at 0 °C. The mixture was stirred at 25 °C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product containing the target compound. Compound 37-1 was purified by high performance liquid chromatography (Waters-spherical-C18-20 μm, 100A, 330 g, mobile phase: acetonitrile-0.5% formic acid aqueous solution, gradient: 11-20%, retention time: 16-27 min, run time: 40 min) to obtain compound 37-1. 1 ¹H NMR (400MHz, DMSO-d6): δ 12.51 (s, 1H), 8.43 (s, 1H), 7.86 (dd, J = 8.8, 2.4Hz, 1H), 7.57 (dd, J = 8.80, 4.4Hz, 1H), 7.18–7.13 (m, 1H), 5.79–5.75 (m, 1H), 4.11–4.04 (m, 1H), 3.84–3.78 (m, 1H), 2.98–2.93 (m, 1H), 2.50–2.43 (m, 1H). ESI-MS theoretical calculation: [M+H] + =219.09, measured value 219.0.

[0425] Step 2

[0426] Compound 37-1 (2.40 g, 11.0 mmol) was dissolved in tetrahydrofuran (90 mL), and a tetrahydrofuran solution of lithium aluminum hydride (44 mL, 110 mmol, 2.5 mol / L) was added dropwise at 0 °C. The reaction mixture was stirred at 60 °C for 3 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and quenched with ice water (4.1 mL). Then, 15% sodium hydroxide aqueous solution (4.1 mL) and water (12.3 mL) were added. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product containing the target compound. This crude product was purified by high-performance liquid chromatography (Waters-spherical-C18-20 μm, 100A, 220 g, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 15-25%, retention time: 20-35 min, run time: 50 min) to obtain compound 37-2. ESI-MS theoretical value: [M+H] + =205.11, measured value 205.0.

[0427] Step 3

[0428] Compound 37-2 (350 mg, 1.71 mmol) was dissolved in N,N-dimethylformamide (5 mL) and acetonitrile (5 mL), and potassium carbonate (709 mg, 5.13 mmol) and 2-(2-bromoethoxy)tetrahydropyran (1.07 g, 5.13 mmol) were added. The mixture was stirred at 25 °C for 16 hours. The reaction solution was extracted with water (20 mL) and ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane / methanol, 10 / 1, v / v) to obtain compound 37-3. ESI-MS theoretical calculation: [M+H] + =333.19, measured value 333.0.

[0429] Step 4

[0430] Compound 37-3 (150 mg, 0.45 mol) was dissolved in tetrahydrofuran (5 mL), and hydrochloric acid aqueous solution (0.90 mL, 0.90 mmol, 1 mol / L) was added. The reaction solution was stirred at 25 °C for 3 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by high performance liquid chromatography (Waters-XBridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 20-30%, retention time: 8.8-10.3 min, run time: 17 min) to obtain compound 37. 1¹H NMR (400MHz, DMSO-d6): δ 10.87 (s, 1H), 7.31–7.24 (m, 2H), 7.18 (s, 1H), 6.90–6.85 (m, 1H), 4.34 (s, 1H), 3.28–3.21 (m, 4H), 2.93–2.88 (m, 1H), 2.78–2.62 (m, 2H), 2.57–2.53 (m, 1H), 2.36–2.25 (m, 1H), 1.95–1.87 (m, 1H), 1.82–1.71 (m, 1H). ESI-MS theoretical calculation: [M+H] + =249.13, measured value 249.0.

[0431] Example 38

[0432] Synthesis route:

[0433] first step

[0434] Compound 38-1 (2.00 g, 9.30 mmol) was dissolved in 1,2-dichloromethane (30 mL), and triethylamine (1.88 g, 18.6 mmol), di-tert-butyl dicarbonate (3.04 g, 14.0 mmol), and 4-dimethylaminopyridine (114 mg, 0.93 mmol) were added. The mixture was stirred at 25 °C for 4 hours. The reaction solution was extracted with saturated ammonium chloride aqueous solution (40 mL) and dichloromethane (30 mL x 3). The organic phases were combined and washed with saturated brine (60 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / dichloromethane, 5 / 1, v / v) to obtain compound 38-2. 1 H NMR (400MHz, DMSO-d6): δ8.13 (dd, J=9.2, 4.0Hz, 1H), 7.65-7.60 (m, 1H), 7.57 (dd, J=8.0, 2.4Hz, 1H), 1.65 (s, 9H).

[0435] Step 2

[0436] In a nitrogen-filled glove box, compound 38-2 (400 mg, 1.60 mmol), (2R)-2-(bromomethyl)azacyclobutane-1-carboxylic acid tert-butyl ester (500 mg, 1.59 mmol), anhydrous sodium carbonate (339 mg, 3.20 mmol), tris(trimethylsilyl)silane (398 mg, 1.60 mmol), nickel chloride dimethoxyethane (17.6 mg, 0.080 mmol), 4,4'-di-tert-butyl-2,2'-dipyridine (21.5 mg, 0.080 mmol), and bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium di(hexafluorophosphate) (18.0 mg, 0.016 mmol) were dissolved in ethylene glycol dimethyl ether (5 mL). The reaction mixture was irradiated with a 34W blue LED (420nm) at 25°C and stirred for 16 hours. After the reaction was complete, the blue light was turned off, and the reaction mixture was extracted with water (50mL) and ethyl acetate (50mL x 3). The organic phases were combined and washed with saturated brine (50mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 1, v / v) to give compound 38-3. ESI-MS theoretical value: [M+H] + =406.21, measured value 406.1.

[0437] Step 3

[0438] Compound 38-3 (880 mg, 2.17 mol) was dissolved in tetrahydrofuran (5 mL), ethanol (5 mL), and water (2 mL). Lithium hydroxide monohydrate (455 mg, 10.9 mmol) was added, and the reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was then extracted with water (50 mL) and ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane / methanol, 20 / 1, v / v) to obtain compound 38-4. 1 ¹H NMR (400MHz, DMSO-d6): δ 12.89 (s, 1H), 7.51–7.43 (m, 2H), 7.23–7.18 (m, 1H), 4.54–4.46 (m, 1H), 3.70–3.64 (m, 1H), 3.55–3.46 (m, 1H), 3.29–3.22 (m, 2H), 2.20–2.13 (m, 1H), 1.98–1.91 (m, 1H), 1.35 (s, 9H). ESI-MS theoretical calculation: [M+H] + =306.15, measured value 306.5.

[0439] Step 4

[0440] Compound 38-4 (560 mg, 1.83 mmol) was dissolved in N,N-dimethylformamide (10 mL). Sodium hydride (87.8 mg, 2.20 mmol, 60% purity) was slowly added at 0 °C under a nitrogen atmosphere. The mixture was stirred at 0 °C for 0.5 h, followed by the addition of p-toluenesulfonyl chloride (419 mg, 2.20 mmol), and the mixture was stirred at 25 °C for 2 h. The reaction mixture was extracted with saturated ammonium chloride aqueous solution (50 mL) and ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1, v / v) to obtain compound 38-5. 1 ¹H NMR (400MHz, DMSO-d⁶): δ 8.10 (dd, J = 9.2, 4.0Hz, 1H), 7.77 (d, J = 8.4Hz, 2H), 7.64–7.59 (m, 1H), 7.57–7.51 (m, 1H), 7.37 (d, J = 8.4Hz, 2H), 4.52–4.48 (m, 1H), 3.64–3.59 (m, 1H), 3.29–3.18 (m, 3H), 2.31 (s, 3H), 2.18–2.13 (m, 1H), 1.78–1.72 (m, 1H), 1.24 (s, 9H). ESI-MS theoretical calculation: [M+H] + =460.16, measured value 460.2.

[0441] Step 5

[0442] Compound 38-5 (630 mg, 1.37 mmol) was dissolved in 1,2-dichloromethane (6 mL), and trifluoroacetic acid (2.0 mL, 26.9 mmol) was slowly added at 0 °C. The mixture was stirred at 25 °C for 2 hours. The reaction solution was extracted with saturated sodium bicarbonate aqueous solution (30 mL) and dichloromethane (30 mL x 3). The organic phases were combined and washed with saturated brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 38-6. ESI-MS theoretical value: [M+H] + =360.11, measured value 360.0.

[0443] Step 6

[0444] Compound 38-6 (200 mg, 0.56 mmol) was dissolved in methanol (5 mL), and N,N-diisopropylethylamine (220 mg, 1.68 mmol) and paraformaldehyde (18.5 mg, 0.62 mmol) were added. The mixture was stirred at 25 °C for 0.5 h. Sodium cyanoborohydride (35.5 mg, 0.57 mmol) was added, and the mixture was stirred at 25 °C for 2 h. The reaction mixture was extracted with saturated sodium bicarbonate aqueous solution (30 mL) and ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane / methanol, 20 / 1, v / v) to give compound 38-7. ESI-MS theoretical calculation: [M+H] + =374.13, measured value 374.0.

[0445] Step 7

[0446] Compound 38-7 (150 mg, 0.40 mol) was dissolved in tetrahydrofuran (1 mL), methanol (1 mL), and water (0.4 mL). Lithium hydroxide monohydrate (83.9 mg, 2.00 mmol) was added, and the reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product containing the target compound. Compound 38 was purified by high performance liquid chromatography (Waters-XBridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 20-30%, retention time: 8.3-9.1 min, run time: 17 min) to obtain compound 38. 1 ¹H NMR (400MHz, DMSO-d⁶): δ 12.78 (s, 1H), 7.52 (dd, J = 9.2, 2.4Hz, 1H), 7.47 (dd, J = 9.2, 4.4Hz, 1H), 7.21–7.17 (m, 1H), 3.27–3.20 (m, 2H), 3.10–3.05 (m, 1H), 3.00–2.96 (m, 1H), 2.63–2.58 (m, 1H), 2.08 (s, 3H), 1.94–1.83 (m, 2H). ESI-MS theoretical calculation: [M+H] + =220.12, measured value 220.0.

[0447] Example 39

[0448] Synthesis route:

[0449] first step

[0450] (R)-N-carboxylic acid tert-butyl ester-azacyclobutane-2-carboxylic acid (1.98 g, 9.83 mmol) was dissolved in dichloromethane (30 mL), and oxalyl chloride (0.683 mL, 11.8 mmol) was added dropwise at 0 °C. The reaction solution was stirred at 0 °C for 10 min, and N,N-dimethylformamide (72.0 mg, 1.04 mmol) was slowly added. The reaction solution was stirred at 25 °C for 1 h. The reaction solution was concentrated under reduced pressure to obtain a crude intermediate. Compound 39-1 (1.00 g, 6.79 mmol) was dissolved in dichloromethane (10 mL), and ethyl magnesium bromide (3.23 mL, 6.45 mmol, 2 mol / L) was slowly added dropwise at 0 °C under a nitrogen atmosphere. The mixture was stirred at 0 °C for 0.5 h. The crude intermediate was dissolved in dichloromethane (20 mL) and added dropwise to the reaction solution at 0 °C. The reaction solution was stirred at 0 °C for 0.5 h. The reaction mixture was extracted with saturated citric acid aqueous solution (50 mL) and dichloromethane (50 mL x 3). The organic phases were combined and washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane / ethyl acetate, 1 / 1, v / v) to give compound 39-2. ESI-MS theoretical calculation: [M+H] + =331.16, measured value 331.0.

[0451] Step 2

[0452] Compound 39-2 (2.99 g, 9.05 mmol) was dissolved in 1,2-dichloromethane (40 mL), and trifluoroacetic acid (10 mL) was slowly added at 0 °C. The mixture was stirred at 25 °C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product containing the target compound. Compound 39-3 was purified by high performance liquid chromatography (Waters-spherical-C18-20 μm, 100A, 330 g, mobile phase: acetonitrile-0.5% formic acid aqueous solution, gradient: 11-20%, retention time: 16-27 min, run time: 40 min) to obtain compound 39-3. 1 ¹H NMR (400MHz, DMSO-d⁶): δ 12.33 (s, 1H), 8.30 (d, J = 3.2Hz, 1H), 7.69 (d, J = 2.4Hz, 1H), 7.45 (d, J = 8.8Hz, 1H), 6.92 (dd, J = 8.8, 2.4Hz, 1H), 5.81–5.75 (m, 1H), 4.11–4.06 (m, 1H), 3.86–3.79 (m, 4H), 2.97–2.91 (m, 1H), 2.51–2.45 (m, 1H). ESI-MS theoretical calculation: [M+H] + =231.11, measured value: 231.0.

[0453] Step 3

[0454] Compound 39-3 (3.00 g, 13.0 mmol) was dissolved in tetrahydrofuran (90 mL), and a tetrahydrofuran solution of lithium aluminum hydride (52.1 mL, 130 mmol, 2.5 mol / L) was added dropwise at 0 °C. The reaction mixture was stirred at 60 °C for 3 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and quenched with ice water (5.2 mL). Then, 15% sodium hydroxide aqueous solution (5.2 mL) and water (15.6 mL) were added. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product containing the target compound. This crude product was purified by high-performance liquid chromatography (Waters-spherical-C18-20 μm, 100A, 220 g, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 15-25%, retention time: 20-35 min, run time: 50 min) to obtain compound 39-4. ESI-MS theoretical value: [M+H] + =217.13, measured value 217.0.

[0455] Step 4

[0456] Compound 39-4 (200 mg, 0.92 mmol) was dissolved in N,N-dimethylformamide (12 mL) and acetonitrile (12 mL), and potassium carbonate (381 mg, 2.76 mmol) and 2-(2-bromoethoxy)tetrahydropyran (577 mg, 2.76 mmol) were added. The mixture was stirred at 25 °C for 24 hours. The reaction solution was extracted with water (50 mL) and ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to give compound 39-5. ESI-MS theoretical calculation: [M+H] + =345.21, measured value 345.1.

[0457] Step 5

[0458] Compound 39-5 (150 mg, 0.44 mol) was dissolved in tetrahydrofuran (5 mL), and hydrochloric acid aqueous solution (0.88 mL, 0.88 mmol, 1 mol / L) was added. The reaction solution was stirred at 25 °C for 3 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by high performance liquid chromatography (Waters-XBridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-0.04% ammonia + 7.5 mmol / L ammonium bicarbonate aqueous solution, gradient: 30-40%, retention time: 6.0-7.8 min, run time: 17 min) to obtain compound 39. 1H NMR (400MHz, DMSO-d6): δ10.59(s,1H),7.19(d,J=8.8Hz,1H),7.04(d,J=2.4Hz ,1H),6.99(d,J=2.4Hz,1H),6.69(dd,J=8.8,2.4Hz,1H),4.33(s,1H),3.75(s, 3H),3.36-3.32(m,2H),3.29-3.25(m,2H),2.94-2.86(m,1H),2.72-2.65(m,2H ),2.58-2.54(m,1H),2.33-2.29(m,1H),1.95-1.89(m,1H),1.85-1.75(m,1H). ESI-MS theoretical calculation value: [M+H] + =261.16, measured value 261.1.

[0459] Example 40

[0460] Synthesis route:

[0461] first step

[0462] Compound 38-6 (400 mg, 1.11 mmol) was dissolved in N,N-dimethylformamide (5 mL), and potassium carbonate (460 mg, 3.33 mmol), 2-bromoethanol (416 mg, 3.33 mmol), and potassium iodide (18.4 mg, 0.11 mmol) were added. The mixture was stirred at 70 °C for 2 hours. The reaction solution was extracted with water (30 mL) and ethyl acetate (30 mL x 3). The organic phases were combined and washed with saturated brine (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane / methanol, 10 / 1, v / v) to give compound 40-1. ESI-MS theoretical calculation: [M+H] + =404.14, measured value 404.0.

[0463] Step 2

[0464] Compound 40-1 (220 mg, 0.55 mol) was dissolved in tetrahydrofuran (1 mL), methanol (1 mL), and water (0.4 mL). Lithium hydroxide monohydrate (115 mg, 2.75 mmol) was added, and the reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by high performance liquid chromatography (Waters-XBridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-0.1% formic acid aqueous solution, gradient: 5-10%, retention time: 5.9-7.7 min, run time: 17 min) to obtain the formate salt of compound 40. 1 ¹H NMR (400MHz, DMSO-d⁶): δ 12.80 (s, 1H), 8.21 (s, 1H), 7.54 (dd, J = 9.2, 2.4Hz, 1H), 7.48 (dd, J = 9.2, 4.4Hz, 1H), 7.23–7.19 (m, 1H), 3.63–3.58 (m, 2H), 3.38–3.32 (m, 2H), 3.23–3.17 (m, 1H), 3.10–3.06 (m, 1H), 2.94–2.87 (m, 1H), 2.65–2.59 (m, 1H), 2.50–2.44 (m, 1H), 1.98–1.85 (m, 2H). ESI-MS theoretical calculation: [M+H] + =250.13, measured value 250.0.

[0465] Example 41

[0466] Synthesis route:

[0467] first step

[0468] Compound 35-1 (250 mg, 0.67 mmol) was dissolved in methanol (5 mL), and diisopropylethylamine (260 mg, 2.01 mmol) and acetaldehyde (118 mg, 1.34 mmol) were added. The mixture was stirred at 25 °C for 0.5 h. Sodium cyanoborohydride (42.5 mg, 0.68 mmol) was added, and the mixture was stirred at 25 °C for 2 h. The reaction mixture was extracted with saturated sodium bicarbonate aqueous solution (20 mL) and ethyl acetate (20 mL x 3). The organic phases were combined and washed with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane / methanol, 10 / 1, v / v) to give compound 41-1. ESI-MS theoretical calculation: [M+H] + =400.16, measured value 400.6.

[0469] Step 2

[0470] Compound 41-1 (160 mg, 0.40 mol) was dissolved in tetrahydrofuran (1.5 mL), methanol (1.5 mL), and water (0.6 mL). Lithium hydroxide monohydrate (83.9 mg, 2.00 mmol) was added, and the reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product containing the target compound. Compound 41 was purified by high performance liquid chromatography (Waters-XBridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 17-30%, retention time: 7.2-9.0 min, run time: 17 min) to obtain compound 41. 1 ¹H NMR (400MHz, DMSO-d⁶): δ 10.81 (s, 1H), 7.61 (d, J = 8.8Hz, 1H), 7.24 (d, J = 2.0Hz, 1H), 6.50 (d, J = 8.4Hz, 1H), 3.86 (s, 3H), 3.31–3.22 (m, 3H), 2.98–2.93 (m, 1H), 2.78–2.73 (m, 1H), 2.59–2.53 (m, 1H), 2.26–2.17 (m, 1H), 1.97–1.73 (m, 2H), 0.91 (t, J = 7.2Hz, 3H). ESI-MS theoretical calculation: [M+H] + =246.15, measured value 246.0.

[0471] Example 42

[0472] Synthesis route:

[0473] first step

[0474] Compound 11-4 (1.60 g, 10.1 mmol) was dissolved in N,N-dimethylformamide (20 mL). Under a nitrogen atmosphere, N-bromosuccinimide (1.88 g, 10.6 mmol) was slowly added at 0 °C, and the mixture was stirred at 25 °C for 1 hour. The reaction solution was extracted with 100 mL of sodium bicarbonate aqueous solution and ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / dichloromethane, 1 / 1, v / v) to give compound 42-1. 1 H NMR (400MHz, DMSO-d6): δ 11.26 (s, 1H), 7.45 (d, J = 2.4Hz, 1H), 7.15 (d, J = 8.8Hz, 1H), 6.68 (d, J = 8.8Hz, 1H), 4.55 (t, J = 8.8Hz, 2H), 3.51 (t, J = 8.8Hz, 2H).

[0475] Step 2

[0476] Compound 42-1 (2.19 g, 9.20 mmol) was dissolved in N,N-dimethylformamide (35 mL). Sodium hydride (442 mg, 11.0 mmol, 60% purity) was slowly added at 0 °C under a nitrogen atmosphere and stirred at 0 °C for 0.5 h. p-Toluenesulfonyl chloride (3.51 g, 18.4 mmol) was added, and the mixture was stirred at 25 °C for 1 h. The reaction mixture was extracted with ammonium chloride aqueous solution (50 mL) and ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / dichloromethane, 4 / 1, v / v) to obtain compound 42-2. 1 H NMR (400MHz, DMSO-d6): δ8.04(s,1H),7.85(d,J=8.8Hz,2H),7.72(d,J=8.8Hz,1H),7.39(d,J =8.0Hz, 2H), 6.88 (d, J = 8.8Hz, 1H), 4.57 (t, J = 8.8Hz, 2H), 3.49 (t, J = 8.8Hz, 2H), 2.32 (s, 3H).

[0477] Step 3

[0478] In a nitrogen-filled glove box, compound 42-2 (300 mg, 0.76 mmol), (2R)-2-(bromomethyl)azacyclobutane-1-carboxylic acid tert-butyl ester (285 mg, 1.14 mmol), anhydrous sodium carbonate (161 mg, 1.52 mmol), tris(trimethylsilyl)silane (283 mg, 1.14 mmol), nickel chloride dimethoxyethane (8.35 mg, 0.038 mmol), 4,4'-di-tert-butyl-2,2'-dipyridine (10.2 mg, 0.038 mmol), and bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium di(hexafluorophosphate) (8.53 mg, 0.008 mmol) were dissolved in ethylene glycol dimethyl ether (4 mL). The reaction solution was irradiated with a 34W blue LED (420nm) at 25°C and stirred for 16 hours. After the reaction was complete, the blue light was turned off, and the reaction solution was extracted with water (30mL) and ethyl acetate (30mL x 3). The organic phases were combined and washed with saturated brine (30mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 1, v / v) to obtain compound 42-3. 1H NMR (400MHz, DMSO-d6): δ7.74(d,J=8.4Hz,2H),7.64(d,J=8.8Hz,1H),7.56(s,1H) ,7.34(d,J=8.0Hz,2H),6.78(d,J=8.8Hz,1H),4.55(t,J=8.8Hz,2H),4.36-4.31(m ,1H), 3.73-3.67(m,1H), 3.63-3.59(m,1H), 3.48-3.37(m,2H), 3.24-3.16(m,1H), 2.92-2.86(m,1H), 2.30(s,3H), 2.13-2.05(m,1H), 1.89-1.83(m,1H), 1.35(s,9H). ESI-MS theoretical calculation value: [M+H-100] + =383.19, measured value 383.1.

[0479] Step 4

[0480] Compound 42-3 (377 mg, 0.78 mmol) was dissolved in dichloromethane (12 mL), and trifluoroacetic acid (4 mL) was slowly added at 0 °C. The mixture was stirred at 25 °C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was extracted with saturated sodium bicarbonate aqueous solution (20 mL) and ethyl acetate (20 mL x 3). The organic phases were combined and washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 42-4. ESI-MS theoretical value: [M+H] + =383.14, measured value: 383.0.

[0481] Step 5

[0482] Compound 42-4 (317 mg, 0.83 mmol) was dissolved in N,N-dimethylformamide (2 mL), and potassium carbonate (344 mg, 2.49 mmol), 2-bromoethanol (311 mg, 2.49 mmol), and potassium iodide (13.8 mg, 0.083 mmol) were added. The mixture was stirred at 70 °C for 2 hours. The reaction solution was extracted with water (20 mL) and ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane / methanol, 10 / 1, v / v) to give compound 42-5. ESI-MS theoretical calculation: [M+H] + =427.16, measured value 427.0.

[0483] Step 6

[0484] Compound 42-5 (150 mg, 0.35 mmol) was dissolved in anhydrous methanol (1.5 mL) and water (1.5 mL), and potassium hydroxide (196 mg, 3.50 mmol) was added. The reaction mixture was stirred at 60 °C for 4 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product containing the target compound. Compound 42-5 was purified by high performance liquid chromatography (Waters-XBridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-0.04% ammonia solution + 7.5 mol / L ammonium bicarbonate solution, gradient: 25-35%, retention time: 7.0-8.3 min, run time: 16 min) to obtain compound 42. 1 ¹H NMR (400MHz, DMSO-d⁶): δ 10.59 (s, 1H), 7.03 (d, J = 8.4Hz, 2H), 6.56 (d, J = 8.4Hz, 1H), 4.51 (t, J = 8.8Hz, 2H), 4.32 (t, J = 5.2Hz, 1H), 3.46 (t, J = 8.8Hz, 2H), 3.27–3.19 (m, 4H), 3.03–2.95 (m, 1H), 2.75–2.63 (m, 2H), 2.59–2.52 (m, 1H), 2.33–2.25 (m, 1H), 1.96–1.89 (m, 1H), 1.82–1.71 (m, 1H). ESI-MS theoretical calculation: [M+H] + =273.15, measured value 273.0.

[0485] Example 43

[0486] Synthesis route:

[0487] first step

[0488] Compound 34-2 (167 mg, 0.35 mmol) was dissolved in tetrahydrofuran (16 mL), and lithium deuterated aluminum hydride (118 mg, 2.80 mmol) was added at 0 °C. The reaction mixture was stirred at 60 °C for 1 hour under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, quenched with ice water (1 mL), and then 15% sodium hydroxide aqueous solution (1 mL) and water (3 mL) were added. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 43-1. ESI-MS theoretical calculation: [M+H] + =389.16, measured value 389.1.

[0489] Step 2

[0490] Compound 43-1 (130 mg, 0.33 mmol) was dissolved in tetrahydrofuran (3 mL), ethanol (3 mL), and water (1 mL). Lithium hydroxide monohydrate (69.2 mg, 1.65 mmol) was added, and the reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by high performance liquid chromatography (Waters-XBridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-0.1% formic acid aqueous solution, gradient: 8-18%, retention time: 7.0-9.5 min, run time: 17 min) to obtain the monoformate salt of compound 43. 1 ¹H NMR (400MHz, DMSO-d⁶): δ 12.51 (s, 1H), 8.24 (s, 1H), 7.35 (d, J = 8.8 Hz, 1H), 7.14 (d, J = 2.0 Hz, 1H), 6.96 (dd, J = 8.8, 2.0 Hz, 1H), 3.78 (s, 3H), 3.29–3.25 (m, 2H), 3.13–3.06 (m, 1H), 3.02–2.96 (m, 1H), 2.74–2.69 (m, 1H), 1.98–1.85 (m, 2H). ESI-MS theoretical calculation: [M+H] + =235.16, measured value 235.0.

[0491] Example 44

[0492] Synthesis route:

[0493] first step

[0494] Compound 44-1 (5.00 g, 37.3 mmol) was dissolved in acetonitrile (50 mL), and potassium carbonate (7.73 g, 55.9 mmol) and 2,2,2-trifluoroethyltrifluoromethanesulfonate (13.0 g, 55.9 mmol) were slowly added. The mixture was stirred at 60 °C for 2 hours. The reaction solution was extracted with water (80 mL) and ethyl acetate (80 mL x 3). The organic phases were combined and washed with saturated brine (80 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1, v / v) to give compound 44-2. 1 ¹H NMR (400MHz, DMSO-d⁶): δ 11.59 (s, 1H), 8.05 (d, J = 2.8Hz, 1H), 7.69 (d, J = 2.8Hz, 1H), 7.48 (d, J = 3.2Hz, 1H), 6.39 (d, J = 3.2Hz, 1H), 4.79 (q, J = 9.2Hz, 2H). ESI-MS theoretical calculation: [M+H]+ =217.05, measured value 217.1.

[0495] Step 2

[0496] (R)-N-carboxylic acid tert-butyl ester-azacyclobutane-2-carboxylic acid (1.98 g, 9.83 mmol) was dissolved in dichloromethane (30 mL), and oxalyl chloride (0.683 mL, 11.8 mmol) was added dropwise at 0 °C. The reaction solution was stirred at 0 °C for 10 min, and N,N-dimethylformamide (72.0 mg, 1.04 mmol) was slowly added. The reaction solution was stirred at 25 °C for 1 h. The reaction solution was concentrated under reduced pressure to obtain a crude intermediate. Compound 44-2 (2.00 g, 9.25 mmol) was dissolved in dichloromethane (20 mL), and ethyl magnesium bromide (4.86 mL, 9.71 mmol, 2 mol / L) was slowly added dropwise at 0 °C under a nitrogen atmosphere. The mixture was stirred at 0 °C for 0.5 h. The crude intermediate was dissolved in dichloromethane (20 mL) and added dropwise to the reaction solution at 0 °C. The reaction solution was stirred at 0 °C for 0.5 h. The reaction mixture was extracted with 30 mL of saturated citric acid aqueous solution and 30 mL x 3 of dichloromethane. The organic phases were combined and washed with 50 mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane / ethyl acetate, 1 / 1, v / v) to give compound 44-3. ESI-MS theoretical value: [M+H] + =400.14, measured value 400.0.

[0497] Step 3

[0498] Compound 44-3 (230 mg, 0.58 mmol) was dissolved in tetrahydrofuran (3 mL), and a tetrahydrofuran solution of lithium aluminum hydride (2.32 mL, 5.80 mmol, 2.5 mol / L) was added dropwise at 0 °C. The reaction mixture was stirred at 60 °C for 8 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and quenched with ice water (0.23 mL). 15% sodium hydroxide aqueous solution (0.23 mL) and water (0.69 mL) were added. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography (Waters-SunFire-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 25-35%, retention time: 8.6-10.0 min, run time: 16 min) to obtain compound 44. 1¹H NMR (400MHz, DMSO-d⁶): δ 11.30 (s, 1H), 8.01 (d, J = 2.8Hz, 1H), 7.71 (d, J = 2.8Hz, 1H), 7.25 (d, J = 2.4Hz, 1H), 4.80 (q, J = 9.2Hz, 2H), 3.27–3.24 (m, 1H), 3.14–3.10 (m, 1H), 2.90–2.84 (m, 1H), 2.78–2.69 (m, 1H), 2.64–2.57 (m, 1H), 2.10 (s, 3H), 1.96–1.88 (m, 1H), 1.85–1.74 (m, 1H). ESI-MS theoretical calculation: [M+H] + =300.12, measured value 300.0.

[0499] Example 45

[0500] Synthesis route:

[0501] first step

[0502] Compound 22-2 (250 mg, 1.15 mmol) was dissolved in methanol (5 mL). Diisopropylethylamine (450 mg, 3.45 mmol) and 2-butanone (415 mg, 5.75 mmol) were added to the reaction solution, and the mixture was stirred at 25 °C for 0.5 hours. Sodium cyanoborohydride (108 mg, 1.72 mmol) was then added, and the mixture was stirred at 25 °C for 2 hours. The reaction solution was then extracted with saturated sodium bicarbonate aqueous solution (30 mL) and dichloromethane (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product containing the target compound. The crude product was purified by high performance liquid chromatography (Waters-XBridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-0.5% ammonia aqueous solution, gradient: 30-50%, retention time: 8.5-10.0 min, run time: 17 min) to obtain compound 45. 1¹H NMR (400MHz, DMSO-d⁶): δ 11.17 (s, 1H), 7.92 (d, J = 2.0Hz, 1H), 7.48 (d, J = 2.0Hz, 1H), 7.20 (s, 1H), 3.82 (s, 3H), 3.27–3.15 (m, 2H), 3.00–2.81 (m, 1H), 2.82–2.74 (m, 1H), 2.68–2.61 (m, 1H), 2.24–2.15 (m, 1H), 1.84–1.76 (m, 1H), 1.72–1.66 (m, 1H), 1.48–1.31 (m, 1H), 1.26–1.04 (m, 1H), 1.02–0.80 (m, 6H). ESI-MS theoretical calculation: [M+H] + =274.18, measured value 274.0.

[0503] Example 46

[0504] Synthesis route:

[0505] first step

[0506] Compound 22-2 (248 mg, 1.14 mmol) was dissolved in methanol (5 mL). Diisopropylethylamine (440 mg, 3.42 mmol) and propionaldehyde (415 mg, 5.75 mmol) were added to the reaction solution. The reaction solution was stirred at 25 °C for 0.5 hours. Sodium cyanoborohydride (108 mg, 1.72 mmol) was added, and the reaction solution was stirred at 25 °C for 2 hours. The reaction solution was extracted with 30 mL of saturated sodium bicarbonate aqueous solution and 30 mL of dichloromethane. The organic phases were combined, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product containing the target compound. The crude product was purified by high performance liquid chromatography (Waters-XBridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate + 0.04% ammonia aqueous solution, gradient: 26-36%, retention time: 8.7-10.8 min, run time: 17 min) to obtain compound 46. 1H NMR (400MHz, DMSO-d6): δ11.16(s,1H),7.92(d,J=2.0Hz,1H),7.51(d,J=2.0 Hz,1H),7.18(s,1H),3.82(s,3H),3.25-3.17(m,2H),2.91-2.86(m,1H),2.7 7-2.72(m,1H),2.60-2.54(m,1H),2.43-2.36(m,1H),2.17-2.05(m,1H),1.9 3-1.88(m,1H),1.82-1.75(m,1H),1.30-1.25(m,2H),0.81(t,J=7.2Hz,3H). ESI-MS theoretical calculation value: [M+H] + =260.17, measured value 260.1.

[0507] Example 47

[0508] Synthesis route:

[0509] first step

[0510] Compound 42-4 (205 mg, 0.54 mmol) was dissolved in N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (210 mg, 1.62 mmol) and acetaldehyde (48.1 mg, 1.08 mmol) were added. The mixture was stirred at 25 °C for 0.5 h. Sodium cyanoborohydride (34.3 mg, 0.55 mmol) was added, and the mixture was stirred at 25 °C for 2 h. The reaction mixture was extracted with 20 mL of saturated sodium bicarbonate aqueous solution and ethyl acetate (20 mL x 3). The organic phases were combined and washed with saturated brine (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane / methanol, 20 / 1, v / v) to give compound 47-1. ESI-MS theoretical calculation: [M+H] + =411.17, measured value 411.0.

[0511] Step 2

[0512] Compound 47-1 (90.0 mg, 0.22 mmol) was dissolved in anhydrous methanol (1.5 mL) and water (1.5 mL), and potassium hydroxide (123 mg, 2.20 mmol) was added. The reaction mixture was stirred at 60 °C for 4 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product containing the target compound. Compound 47-1 was purified by high performance liquid chromatography (Waters-XBridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 20-35%, retention time: 8.0-9.7 min, run time: 17 min) to obtain compound 47. 1 H NMR (400MHz, DMSO-d6): δ10.59(s,1H),7.08-6.98(m,2H),6.56(d,J=8.4Hz,1H) ,4.51(t,J=8.8Hz,2H),3.46(t,J=8.8Hz,2H),3.26-3.21(m,1H),3.15-3.08(m, 1H),3.04-2.96(m,1H),2.75-2.70(m,1H),2.58-2.52(m,1H),2.50-2.43(m,1H) ,2.21-2.12(m,1H),1.93-1.86(m,1H),1.78-1.69(m,1H),0.86(t,J=7.2Hz,3H). ESI-MS theoretical calculation value: [M+H] + =257.16, measured value 257.0.

[0513] Example 48

[0514] Synthesis route:

[0515] first step

[0516] Compound 9-2 (5.00 g, 15.7 mmol) was dissolved in 1,2-dichloromethane (50 mL), and trifluoroacetic acid (17 mL) was slowly added at 0 °C. The mixture was stirred at 25 °C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product containing the target compound. Compound 48-1 was purified by high performance liquid chromatography (Waters-spherical-C18-20 μm, 100A, 330 g, mobile phase: acetonitrile-0.5% formic acid aqueous solution, gradient: 11-20%, retention time: 16-27 min, run time: 40 min) to obtain compound 48-1. 1¹H NMR (400MHz, DMSO-d⁶): δ 13.11 (s, ¹H), 9.21 (s, ¹H), 8.62 (s, ¹H), 8.44–8.42 (m, ¹H), 8.25 (dd, J = 9.2, 2.8Hz, ¹H), 5.82 (t, J = 8.0Hz, ¹H), 4.12–4.06 (m, ¹H), 3.85–3.80 (m, ¹H), 2.99–2.94 (m, ¹H), 2.56–2.53 (m, ¹H). ESI-MS theoretical calculation: [M+H] + =220.08, measured value: 220.0.

[0517] Step 2

[0518] Compound 48-1 (4.80 g, 21.9 mmol) was dissolved in tetrahydrofuran (90 mL), and a solution of lithium aluminum hydride in tetrahydrofuran (87.6 mL, 219 mmol, 2.5 mol / L) was added dropwise at 0 °C. The reaction mixture was stirred at 60 °C for 6 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and quenched with ice water (8.4 mL). Then, 15% sodium hydroxide aqueous solution (8.4 mL) and water (25.2 mL) were added. The mixture was filtered, and the filtrate was concentrated under reduced pressure. Compound 48-2 was purified by high-performance liquid chromatography (Waters-spherical-C18-20 μm, 100A, 220 g, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 7.8-25%, retention time: 15-35 min, run time: 50 min). ESI-MS theoretical value: [M+H] + =206.10, measured value: 206.1.

[0519] Step 3

[0520] Compound 48-2 (114 mg, 0.56 mmol) was dissolved in ethanol (3.0 mL), and diisopropylethylamine (217 mg, 1.68 mmol) and methyl vinyl sulfone (178 mg, 1.68 mmol) were added. The mixture was stirred at 25 °C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product containing the target compound. Compound 48 was purified by high performance liquid chromatography (Waters-XBridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 25-35%, retention time: 7.4-8.2 min, run time: 17 min) to obtain compound 48. 1¹H NMR (400MHz, DMSO-d⁶): δ 11.51 (s, 1H), 8.15–8.13 (m, 1H), 7.89 (dd, J = 9.2, 2.8Hz, 1H), 7.36 (d, J = 2.4Hz, 1H), 3.29–3.26 (m, 2H), 3.13–3.04 (m, 2H), 3.01 (s, 3H), 2.96–2.85 (m, 2H), 2.77–2.66 (m, 2H), 2.61–2.54 (m, 1H), 1.94–1.87 (m, 1H), 1.81–1.75 (m, 1H). ESI-MS theoretical calculation: [M+H] + =312.11, measured value 312.0.

[0521] Example 49

[0522] Synthesis route:

[0523] first step

[0524] Compound 49-1 (2.50 g, 13.4 mmol) was dissolved in N,N-dimethylformamide (25 mL). Under a nitrogen atmosphere, N-bromosuccinimide (2.51 g, 14.1 mmol) was slowly added at 0 °C, and the mixture was stirred at 25 °C for 1 hour. The reaction mixture was extracted with 100 mL of sodium bicarbonate aqueous solution and ethyl acetate (100 mL x 3). The organic phases were combined and washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / dichloromethane, 1 / 1, v / v) to give compound 49-2. ESI-MS theoretical value: [M+H] + =264.95 and 266.95, actual values ​​264.9 and 266.9.

[0525] Step 2

[0526] Compound 49-2 (3.00 g, 11.3 mmol) was dissolved in N,N-dimethylformamide (30 mL). Sodium hydride (543 mg, 13.6 mmol, 60% purity) was slowly added at 0 °C under a nitrogen atmosphere and stirred at 0 °C for 0.5 h. p-Toluenesulfonyl chloride (4.32 g, 22.6 mmol) was added, and the mixture was stirred at 25 °C for 0.5 h. The reaction mixture was extracted with ammonium chloride aqueous solution (50 mL) and ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / dichloromethane, 4 / 1, v / v) to obtain compound 49-3. 1H NMR (400MHz, DMSO-d6): δ 8.86 (s, 1H), 8.45 (s, 1H), 8.34 (s, 1H), 8.05 (d, J = 8.4Hz, 2H), 7.46 (d, J = 8.4Hz, 2H), 2.36 (s, 3H).

[0527] Step 3

[0528] In a nitrogen-filled glove box, compound 49-3 (200 mg, 0.48 mmol), (2R)-2-(bromomethyl)azacyclobutane-1-carboxylic acid tert-butyl ester (180 mg, 0.72 mmol), anhydrous sodium carbonate (110 mg, 0.96 mmol), tris(trimethylsilyl)silane (179 mg, 0.72 mmol), nickel chloride dimethoxyethane (5.27 mg, 0.024 mmol), 4,4'-di-tert-butyl-2,2'-dipyridine (6.44 mg, 0.024 mmol), and bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium di(hexafluorophosphate) (5.39 mg, 0.005 mmol) were dissolved in ethylene glycol dimethyl ether (4 mL). The reaction mixture was irradiated with a 34W blue LED (420nm) at 25°C and stirred for 16 hours. After the reaction was complete, the blue light was turned off, and the reaction mixture was extracted with water (30mL) and ethyl acetate (30mL x 3). The organic phases were combined and washed with saturated brine (30mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 1, v / v) to give compound 49-4. ESI-MS theoretical value: [M+H] + =510.16, measured value 510.1.

[0529] Step 4

[0530] Compound 49-4 (310 mg, 0.61 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (1 mL) was slowly added at 0 °C. The mixture was stirred at 25 °C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was extracted with saturated sodium bicarbonate aqueous solution (20 mL) and ethyl acetate (20 mL x 3). The organic phases were combined and washed with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 49-5. ESI-MS theoretical value: [M+H] + =410.11, measured value: 410.0.

[0531] Step 5

[0532] Compound 49-5 (290 mg, 0.71 mmol) was dissolved in methanol (5 mL), and N,N-diisopropylethylamine (280 mg, 2.13 mmol) and paraformaldehyde (23.5 mg, 0.78 mmol) were added. The mixture was stirred at 25 °C for 0.5 h. Sodium cyanoborohydride (45.1 mg, 0.72 mmol) was added, and the mixture was stirred at 25 °C for 2 h. The reaction mixture was extracted with water (20 mL) and ethyl acetate (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane / methanol, 20 / 1, v / v) to give compound 49-6. ESI-MS theoretical calculation: [M+H] + =424.12, measured value 424.1.

[0533] Step 6

[0534] Compound 49-6 (80.0 mg, 0.19 mmol) was dissolved in tetrahydrofuran (0.5 mL), methanol (0.5 mL), and water (0.5 mL). Sodium hydroxide (38.0 mg, 0.95 mmol) was added, and the reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product containing the target compound. Compound 49 was purified by high performance liquid chromatography (Waters-XBridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 20-35%, retention time: 8.0-9.7 min, run time: 17 min) to obtain compound 49. 1 ¹H NMR (400MHz, DMSO-d⁶): δ 11.98 (s, 1H), 8.51 (d, J = 2.0Hz, 1H), 8.36 (d, J = 2.0Hz, 1H), 7.46 (s, 1H), 3.23–3.20 (m, 1H), 3.15–3.09 (m, 1H), 2.96–2.90 (m, 1H), 2.84–2.78 (m, 1H), 2.63–2.56 (m, 1H), 2.07 (s, 3H), 1.95–1.87 (m, 1H), 1.81–1.74 (m, 1H). ESI-MS theoretical calculation: [M+H] + =270.11, measured value 269.9.

[0535] Example 50

[0536] Synthesis route:

[0537] first step

[0538] Compound 48-2 (150 mg, 0.58 mmol) was dissolved in methanol (1.5 mL). Diisopropylethylamine (225 mg, 1.74 mmol) and isobutyraldehyde (125 mg, 1.74 mmol) were added to the reaction solution. The reaction solution was stirred at 25 °C for 0.5 hours. Sodium cyanoborohydride (36.5 mg, 0.58 mmol) was added, and the reaction solution was stirred at 25 °C for 2 hours. The reaction solution was extracted with 20 mL of saturated sodium bicarbonate aqueous solution and 3 x dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product containing the target compound. The crude product was purified by high performance liquid chromatography (Waters-XBridge-C18-10μm-19*250mm, mobile phase: acetonitrile-10mmol / L ammonium bicarbonate aqueous solution, gradient: 30-45%, retention time: 8.6-10.8min, run time: 17min) to obtain compound 50. 1 ¹H NMR (400MHz, DMSO-d⁶): δ 11.48 (s, 1H), 8.14–8.13 (m, 1H), 7.84–7.81 (m, 1H), 7.33 (d, J = 2.4Hz, 1H), 3.25–3.17 (m, 2H), 2.88–2.82 (m, 1H), 2.77–2.70 (m, 1H), 2.60–2.54 (m, 1H), 2.20–2.14 (m, 1H), 2.03–1.98 (m, 1H), 1.90–1.85 (m, 1H), 1.79–1.73 (m, 1H), 1.53–1.47 (m, 1H), 0.82–0.77 (m, 6H). ESI-MS theoretical calculation: [M+H] + =262.16, measured value 262.1.

[0539] Example 51

[0540] Synthesis route:

[0541] first step

[0542] Compound 48-2 (150 mg, 0.58 mmol) was dissolved in methanol (1.5 mL). Diisopropylethylamine (225 mg, 1.74 mmol) and propionaldehyde (101 mg, 1.74 mmol) were added to the reaction solution, and the mixture was stirred at 25 °C for 0.5 hours. Sodium cyanoborohydride (36.5 mg, 0.58 mmol) was added, and the mixture was stirred at 25 °C for 2 hours. The reaction solution was then extracted with saturated sodium bicarbonate aqueous solution (20 mL) and dichloromethane (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product containing the target compound. The crude product was purified by high performance liquid chromatography (Waters-XBridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 25-35%, retention time: 7.7-9.8 min, run time: 17 min) to obtain compound 51. 1 ¹H NMR (400MHz, DMSO-d⁶): δ 11.49 (s, 1H), 8.15–8.13 (m, 1H), 7.83 (dd, J = 9.6, 2.4Hz, 1H), 7.33 (d, J = 2.4Hz, 1H), 3.25–3.17 (m, 2H), 2.91–2.85 (m, 1H), 2.78–2.71 (m, 1H), 2.60–2.53 (m, 1H), 2.41–2.34 (m, 1H), 2.14–2.08 (m, 1H), 1.92–1.85 (m, 1H), 1.78–1.72 (m, 1H), 1.30–1.24 (m, 2H), 0.81 (t, J = 7.2Hz, 3H). ESI-MS theoretical calculation: [M+H] + =248.15, measured value 248.0.

[0543] Example 52

[0544] Synthesis route:

[0545] first step

[0546] Compound 48-2 (150 mg, 0.58 mmol) was dissolved in methanol (2 mL). Diisopropylethylamine (225 mg, 1.74 mmol) and acetaldehyde (76.7 mg, 1.74 mmol) were added to the reaction solution, and the mixture was stirred at 25 °C for 0.5 hours. Sodium cyanoborohydride (36.5 mg, 0.58 mmol) was added, and the mixture was stirred at 25 °C for 2 hours. The reaction solution was then extracted with saturated sodium bicarbonate aqueous solution (20 mL) and dichloromethane (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product containing the target compound. The crude product was purified by high performance liquid chromatography (Waters-XBridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 20-30%, retention time: 7.4-9.2 min, run time: 17 min) to obtain compound 52. 1 ¹H NMR (400MHz, DMSO-d⁶): δ 11.48 (s, 1H), 8.14–8.13 (m, 1H), 7.83 (dd, J = 9.6, 2.4Hz, 1H), 7.33 (d, J = 2.4Hz, 1H), 3.24–3.16 (m, 2H), 2.91–2.86 (m, 1H), 2.78–2.72 (m, 1H), 2.58–2.52 (m, 1H), 2.48–2.41 (m, 1H), 2.17–2.13 (m, 1H), 1.90–1.86 (m, 1H), 1.79–1.72 (m, 1H), 0.84 (t, J = 7.2Hz, 3H). ESI-MS theoretical calculation: [M+H] + =234.13, measured value 234.0.

[0547] Example 53

[0548] Synthesis route:

[0549] first step

[0550] Compound 48-2 (800 mg, 3.12 mmol) was dissolved in 1,2-dichloromethane (8 mL), and triethylamine (950 mg, 9.36 mmol) and di-tert-butyl dicarbonate (820 mg, 3.74 mmol) were added. The mixture was stirred at 25 °C for 1 hour. The reaction solution was extracted with saturated ammonium chloride aqueous solution (40 mL) and dichloromethane (30 mL x 3). The organic phases were combined and washed with saturated brine (60 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / dichloromethane, 3 / 1, v / v) to give compound 53-1. 1¹H NMR (400MHz, DMSO-d⁶): δ 8.56 (s, 1H), 8.18–8.17 (m, 1H), 7.63 (d, J = 7.6Hz, 1H), 7.18 (d, J = 2.4Hz, 1H), 4.52–4.47 (m, 1H), 3.80–3.75 (m, 1H), 3.62–3.58 (m, 1H), 3.23–3.15 (m, 2H), 2.19–2.14 (m, 1H), 1.90–1.82 (m, 1H), 1.46 (s, 9H). ESI-MS theoretical calculation: [M+H] + =306.15, measured value 306.0.

[0551] Step 2

[0552] Compound 53-1 (90.0 mg, 0.25 mmol) was dissolved in tetrahydrofuran (9 mL), and lithium deuterated aluminum hydride (84.0 mg, 2.00 mmol) was added in portions at 0 °C. The reaction mixture was stirred at 60 °C for 1 hour under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and quenched with ice water (0.8 mL). 15% sodium hydroxide aqueous solution (0.8 mL) and water (2.4 mL) were added. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography (Waters-XBridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 15-25%, retention time: 8.6-9.9 min, run time: 17 min) to obtain compound 53. 1 ¹H NMR (400MHz, DMSO-d⁶): δ 11.49 (s, 1H), 8.15–8.14 (m, 1H), 7.83 (dd, J = 9.6, 2.4Hz, 1H), 7.33 (d, J = 2.4Hz, 1H), 3.22–3.19 (m, 1H), 3.12–3.07 (m, 1H), 2.88–2.83 (m, 1H), 2.76–2.71 (m, 1H), 2.63–2.57 (m, 1H), 1.94–1.87 (m, 1H), 1.81–1.74 (m, 1H). ESI-MS theoretical calculation: [M+H] + =223.14, measured value 223.0.

[0553] Example 54

[0554] Synthesis route:

[0555] first step

[0556] Compound 39-4 (150 mg, 0.69 mmol) was dissolved in methanol (1.5 mL). Diisopropylethylamine (268 mg, 2.07 mmol) and acetaldehyde (91.2 mg, 2.07 mmol) were added to the reaction solution, and the mixture was stirred at 25 °C for 0.5 hours. Sodium cyanoborohydride (43.4 mg, 0.69 mmol) was added, and the mixture was stirred at 25 °C for 2 hours. The reaction solution was then extracted with saturated sodium bicarbonate aqueous solution (20 mL) and dichloromethane (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product containing the target compound. The crude product was purified by high performance liquid chromatography (Waters-XBridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 28-38%, retention time: 8.5-9.7 min, run time: 17 min) to obtain compound 54. 1 ¹H NMR (400MHz, DMSO-d⁶): δ 10.59 (s, 1H), 7.19 (d, J = 8.8Hz, 1H), 7.04 (d, J = 2.4Hz, 1H), 6.98 (d, J = 2.4Hz, 1H), 6.69 (dd, J = 8.8, 2.4Hz, 1H), 3.75 (s, 3H), 3.25–3.16 (m, 2H), 2.92–2.87 (m, 1H), 2.75–2.70 (m, 1H), 2.58–2.51 (m, 2H), 2.18–2.14 (m, 1H), 1.93–1.90 (m, 1H), 1.78–1.74 (m, 1H), 0.87 (t, J = 7.2Hz, 3H). ESI-MS theoretical calculation: [M+H] + =245.16, measured value 245.1.

[0557] Example 55

[0558] Synthesis route:

[0559] first step

[0560] Compound 39-4 (150 mg, 0.69 mmol) was dissolved in methanol (1.5 mL). Diisopropylethylamine (268 mg, 2.07 mmol) and propionaldehyde (120 mg, 2.07 mmol) were added to the reaction solution, and the mixture was stirred at 25 °C for 0.5 hours. Sodium cyanoborohydride (43.4 mg, 0.69 mmol) was then added, and the mixture was stirred at 25 °C for 2 hours. The reaction solution was then extracted with saturated sodium bicarbonate aqueous solution (20 mL) and dichloromethane (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product containing the target compound. The crude product was purified by high performance liquid chromatography (Waters-XBridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 32-42%, retention time: 8.0-9.0 min, run time: 17 min) to obtain compound 55. 1 H NMR (400MHz, DMSO-d6): δ10.59(s,1H),7.20(d,J=8.8Hz,1H),7.04(d,J=2.4Hz,1H),6 .98(d,J=2.4Hz,1H),6.69(dd,J=8.8,2.4Hz,1H),3.75(s,3H),3.25-3.16(m,2H),2.9 1-2.87 (m, 1H), 2.75-2.70 (m, 1H), 2.58-2.51 (m, 1H), 2.49-2.40 (m, 1H), 2.16-2.07 (m, 1H), 1.92-1.90 (m, 1H), 1.79-1.75 (m, 1H), 1.32-1.26 (m, 2H), 0.82 (t, J = 7.2 Hz, 3H). ESI-MS theoretical calculation: [M+H] + =259.17, measured value 259.1.

[0561] Example 56

[0562] Synthesis route:

[0563] first step

[0564] Compound 39-4 (100 mg, 0.46 mmol) was dissolved in acetonitrile (3 mL). Potassium carbonate (191 mg, 1.38 mmol) and iodopropane (157 mg, 0.92 mmol) were added to the reaction solution, and the reaction solution was stirred at 70 °C for 2 hours. The reaction solution was cooled to room temperature, and water (20 mL) was added. Dichloromethane (20 mL x 3) was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product containing the target compound. The crude product was purified by high performance liquid chromatography (Waters-XBridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 25-40%, retention time: 7.3-8.9 min, run time: 17 min) to obtain compound 56. 1 H NMR (400MHz, DMSO-d6): δ10.60(s,1H),7.20(d,J=8.8Hz,1H),7.05(d,J=2.4Hz,1 H),6.95(d,J=2.4Hz,1H),6.70(dd,J=8.8,2.4Hz,1H),3.75(s,3H),3.29-3.18(m, 2H), 2.96-2.91(m,1H), 2.80-2.73(m,1H), 2.65-2.59(m,1H), 2.40-2.36(m,1H), 1.85-1.82(m,1H), 1.70-1.68(m,1H), 1.02(d,J=6.4Hz,3H), 0.85(d,J=6.4Hz,3H). ESI-MS theoretical calculation: [M+H] + =259.17, measured value 259.1.

[0565] Example 57

[0566] Synthesis route:

[0567] first step

[0568] Compound 37-2 (150 mg, 0.73 mmol) was dissolved in methanol (3 mL). Diisopropylethylamine (377 mg, 2.92 mmol) and acetaldehyde (161 mg, 3.65 mmol) were added to the reaction solution, and the mixture was stirred at 25 °C for 0.5 hours. Sodium cyanoborohydride (45.9 mg, 0.73 mmol) was added, and the mixture was stirred at 25 °C for 2 hours. The reaction solution was then extracted with saturated sodium bicarbonate aqueous solution (20 mL) and dichloromethane (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product containing the target compound. The crude product was purified by high performance liquid chromatography (Waters-XBridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 23-35%, retention time: 6.9-8.2 min, run time: 17 min) to obtain compound 57. 1 H NMR (400MHz, DMSO-d6): δ10.87(s,1H),7.31-7.28(m,1H),7.24-7.21(m,1H), 7.17(d,J=4.0Hz,1H),6.90-6.85(m,1H),3.25-3.21(m,1H),3.18-3.15(m,1H) ,2.92-2.87(m,1H),2.75-2.70(m,1H),2.57-2.52(m,1H),2.48-2.44(m,1H),2 .18-2.13(m,1H),1.92-1.86(m,1H),1.79-1.72(m,1H),0.86(t,J=6.4Hz,3H). ESI-MS theoretical calculation value: [M+H] + =233.14, measured value 233.0.

[0569] Example 58

[0570] Synthesis route:

[0571] first step

[0572] Compound 37-2 (150 mg, 0.73 mmol) was dissolved in methanol (3 mL). Diisopropylethylamine (377 mg, 2.92 mmol) and propionaldehyde (127 mg, 2.19 mmol) were added to the reaction solution, and the mixture was stirred at 25 °C for 0.5 hours. Sodium cyanoborohydride (45.9 mg, 0.73 mmol) was added, and the mixture was stirred at 25 °C for 2 hours. The reaction solution was then extracted with saturated sodium bicarbonate aqueous solution (20 mL) and dichloromethane (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product containing the target compound. The crude product was purified by high performance liquid chromatography (Waters-XBridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 32-42%, retention time: 8.0-9.0 min, run time: 17 min) to obtain compound 58. 1 H NMR (400MHz, DMSO-d6): δ10.88(s,1H),7.31-7.28(m,1H),7.29-7.24(m,1H),7.17 (d,J=4.0Hz,1H),6.90-6.85(m,1H),3.25-3.21(m,1H),3.17-3.13(m,1H),2.91-2. 86 (m, 1H), 2.75-2.70 (m, 1H), 2.57-2.53 (m, 1H), 2.42-2.37 (m, 1H), 2.14-2.09 (m, 1H), 1.90-1.87 (m, 1H), 1.77-1.73 (m, 1H), 1.30-1.23 (m, 2H), 0.82 (t, J = 6.4 Hz, 3H). ESI-MS theoretical calculation: [M+H] + =247.15, measured value 247.0.

[0573] Example 59

[0574] Synthesis route:

[0575] first step

[0576] Compound 37-2 (120 mg, 0.59 mmol) was dissolved in acetonitrile (3 mL). Potassium carbonate (245 mg, 1.77 mmol) and 2-iodopropane (201 mg, 1.18 mmol) were added to the reaction solution, and the reaction solution was stirred at 70 °C for 4 hours. The reaction solution was cooled to room temperature, and water (20 mL) and dichloromethane (20 mL x 3) were added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product containing the target compound. The crude product was purified by high performance liquid chromatography (Waters-XBridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 15-40%, retention time: 7.8-9.4 min, run time: 17 min) to obtain compound 59. 1 ¹H NMR (400MHz, DMSO-d⁶): δ 10.89 (s, 1H), 7.30 (dd, J = 8.8, 4.0Hz, 1H), 7.23–7.19 (m, 2H), 6.91–6.86 (m, 1H), 3.32–3.25 (m, 1H), 3.24–3.21 (m, 1H), 2.96–2.93 (m, 1H), 2.77–2.71 (m, 1H), 2.64–2.61 (m, 1H), 2.39–2.35 (m, 1H), 1.83–1.79 (m, 1H), 1.70–1.66 (m, 1H), 1.01 (d, J = 6.4Hz, 3H), 0.84 (d, J = 6.4Hz, 3H). ESI-MS theoretical calculation: [M+H] + =247.15, measured value 247.0.

[0577] Example 60

[0578] Synthesis route:

[0579] first step

[0580] Compound 39-4 (100 mg, 0.46 mmol) was dissolved in methanol (1 mL). Diisopropylethylamine (178 mg, 1.38 mmol) and isobutyraldehyde (99.5 mg, 1.38 mmol) were added to the reaction solution, and the mixture was stirred at 25 °C for 0.5 hours. Sodium cyanoborohydride (28.9 mg, 0.46 mmol) was added, and the mixture was stirred at 25 °C for 2 hours. The reaction solution was then extracted with saturated sodium bicarbonate aqueous solution (20 mL) and dichloromethane (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product containing the target compound. The crude product was purified by high performance liquid chromatography (Waters-XBridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 35-45%, retention time: 7.7-9.6 min, run time: 17 min) to obtain compound 60. 1 H NMR (400MHz, DMSO-d6): δ10.59(s,1H),7.20(d,J=8.8Hz,1H),7.05(d,J=2.4Hz,1H),6.95 (d,J=2.4Hz,1H),6.69(dd,J=8.8,2.4Hz,1H),3.75(s,3H),3.32-3.24(m,1H),3.21-3.17 (m, 1H), 2.90-2.85(m, 1H), 2.75-2.67(m, 1H), 2.59-2.52(m, 1H), 2.26-2.21(m, 1H), 2.04-2.00(m, 1H), 1.91-1.87(m, 1H), 1.81-1.76(m, 1H), 1.57-1.51(m, 1H), 0.85-0.82(m, 6H). ESI-MS theoretical calculation: [M+H] + =273.19, measured value 273.1.

[0581] Example 61

[0582] Synthesis route:

[0583] first step

[0584] Compound 22-2 (100 mg, 0.46 mmol) was dissolved in methanol (2 mL). Diisopropylethylamine (178 mg, 1.38 mmol) and isobutyraldehyde (99.5 mg, 1.38 mmol) were added to the reaction solution, and the mixture was stirred at 25 °C for 0.5 hours. Sodium cyanoborohydride (28.9 mg, 0.46 mmol) was added, and the mixture was stirred at 25 °C for 2 hours. The reaction solution was then extracted with saturated sodium bicarbonate aqueous solution (30 mL) and dichloromethane (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product containing the target compound. The crude product was purified by high performance liquid chromatography (Waters-XBridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 35-45%, retention time: 5.0-7.3 min, run time: 16 min) to obtain compound 61. 1 H NMR (400MHz, DMSO-d6): δ11.15(s,1H),7.92(d,J=2.4Hz,1H),7.50(d,J=2.4H z,1H),7.17(d,J=2.0Hz,1H),3.82(s,3H),3.27-3.19(m,2H),2.88-2.83(m,1 H),2.78-2.73(m,1H),2.60-2.55(m,1H),2.20-2.17(m,1H),2.04-2.00(m,1H ),1.92-1.88(m,1H),1.82-1.75(m,1H),1.56-1.46(m,1H),0.84-0.77(m,6H). ESI-MS theoretical calculation value: [M+H] + =274.18, measured value 274.0.

[0585] Example 62

[0586] Synthesis route:

[0587] first step

[0588] Compound 37-2 (150 mg, 0.73 mmol) was dissolved in methanol (3 mL). Diisopropylethylamine (377 mg, 2.92 mmol) and isobutyraldehyde (158 mg, 2.19 mmol) were added to the reaction solution, and the mixture was stirred at 25 °C for 0.5 hours. Sodium cyanoborohydride (45.9 mg, 0.73 mmol) was added, and the mixture was stirred at 25 °C for 2 hours. The reaction solution was then extracted with saturated sodium bicarbonate aqueous solution (20 mL) and dichloromethane (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product containing the target compound. The crude product was purified by high performance liquid chromatography (Waters-XBridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 44-60%, retention time: 6.7-9.4 min, run time: 17 min) to obtain compound 62. 1 H NMR (400MHz, DMSO-d6): δ10.87(s,1H),7.30(dd,J=8.8,4.4Hz,1H),7.25(dd,J=9.8,2.4H z,1H),7.17(d,J=2.4Hz,1H),6.87(td,J=9.2,2.4Hz,1H),3.26-3.23(m,1H),3.18-3.14( (m, 1H), 2.89-2.84 (m, 1H), 2.75-2.69 (m, 1H), 2.58-2.54 (m, 1H), 2.23-2.18 (m, 1H), 2.03-1.98 (m, 1H), 1.90-1.87 (m, 1H), 1.79-1.74 (m, 1H), 1.54-1.50 (m, 1H), 0.83-0.80 (m, 6H). ESI-MS theoretical calculation: [M+H] + =261.17, measured value 261.1.

[0589] Example 63

[0590] Synthesis route:

[0591] first step

[0592] Compound 63-1 (1.00 g, 4.95 mmol) was dissolved in N,N-dimethylformamide (25 mL). Under a nitrogen atmosphere, N-bromosuccinimide (925 mg, 5.20 mmol) was slowly added at 0 °C, and the mixture was stirred at 25 °C for 1 hour. The reaction solution was extracted with 50 mL of sodium bicarbonate aqueous solution and 3 x ethyl acetate. The combined organic phases were washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / dichloromethane, 1 / 1, v / v) to give compound 63-2. ESI-MS theoretical value: [M+H] + =280.95 and 282.95, actual values ​​280.8 and 282.8.

[0593] Step 2

[0594] Compound 63-2 (1.66 g, 5.91 mmol) was dissolved in dichloromethane (15 mL), and N,N-diisopropylethylamine (1.15 g, 8.87 mmol), di-tert-butyl dicarbonate (1.93 g, 8.87 mmol), and 4-dimethylaminopyridine (220 mg, 1.77 mmol) were added. The mixture was stirred at 25 °C for 2 hours. The reaction solution was extracted with ammonium chloride aqueous solution (50 mL) and dichloromethane (50 mL x 3). The organic phases were combined and washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / dichloromethane, 5 / 1, v / v) to obtain compound 63-3. 1 H NMR (400MHz, DMSO-d6): δ8.56 (d, J = 2.4 Hz, 1H), 8.20 (s, 1H), 8.02 (d, J = 1.6 Hz, 1H), 1.61 (s, 9H).

[0595] Step 3

[0596] In a nitrogen-filled glove box, compound 63-3 (200 mg, 0.52 mmol), (2R)-2-(bromomethyl)azacyclobutane-1-carboxylic acid tert-butyl ester (260 mg, 1.04 mmol), anhydrous sodium carbonate (110 mg, 1.04 mmol), tris(trimethylsilyl)silane (259 mg, 1.04 mmol), nickel chloride dimethoxyethane (5.71 mg, 0.026 mmol), 4,4'-di-tert-butyl-2,2'-dipyridine (6.98 mg, 0.026 mmol), and bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium di(hexafluorophosphate) (5.83 mg, 0.0052 mmol) were dissolved in ethylene glycol dimethyl ether (4 mL). The reaction mixture was irradiated with a 34W blue LED (420nm) at 25°C and stirred for 16 hours. After the reaction was complete, the blue light was turned off, and the reaction mixture was extracted with water (20mL) and ethyl acetate (20mL x 3). The organic phases were combined and washed with saturated brine (20mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 1, v / v) to give compound 63-4. ESI-MS theoretical calculation: [M+H] + =472.20, measured value 472.2.

[0597] Step 4

[0598] Compound 63-4 (731 mg, 1.55 mmol) was dissolved in tetrahydrofuran (5 mL), ethanol (5 mL), and water (2 mL). Lithium hydroxide monohydrate (325 mg, 7.75 mmol) was added, and the reaction mixture was stirred at 60 °C for 2 hours. The mixture was extracted with water (20 mL) and ethyl acetate (20 mL x 3). The organic phases were combined and washed with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane / methanol, 20 / 1, v / v) to give compound 63-5. ESI-MS theoretical value: [M+H] + =372.15, measured value: 372.1.

[0599] Step 5

[0600] Compound 63-5 (210 mg, 0.57 mmol) was dissolved in tetrahydrofuran (5 mL), and a tetrahydrofuran solution of lithium aluminum hydride (2.28 mL, 5.70 mmol, 2.5 mol / L) was added dropwise at 0 °C. The reaction mixture was stirred at 60 °C for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and quenched with ice water (0.25 mL). A 15% sodium hydroxide aqueous solution (0.25 mL) and water (0.75 mL) were added, and the mixture was filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by high performance liquid chromatography (Waters-SunFire-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 27-42%, retention time: 8.2-9.8 min, run time: 16 min) to obtain compound 63. 1 ¹H NMR (400MHz, DMSO-d⁶): δ 11.72 (s, 1H), 8.21 (d, J = 2.4Hz, 1H), 8.04 (d, J = 1.2Hz, 1H), 7.41 (s, 1H), 3.24–3.18 (m, 1H), 3.12–3.08 (m, 1H), 2.91–2.86 (m, 1H), 2.80–2.76 (m, 1H), 2.61–2.57 (m, 1H), 2.07 (s, 3H), 1.93–1.88 (m, 1H), 1.79–1.72 (m, 1H). ESI-MS theoretical calculation: [M+H] + =286.11, measured value 285.9.

[0601] Example 64

[0602] Synthesis route:

[0603] first step

[0604] Sodium hydride (9.50 g, 238 mmol, 60% purity) was dissolved in N,N-dimethylformamide (380 mL). Compound 64-1 (36.0 g, 183 mmol) was slowly added at 0 °C under a nitrogen atmosphere and stirred at 0 °C for 0.5 h. Then, p-triisopropylchlorosilane (52.8 g, 274 mmol) was added and stirred at 70 °C for 3 h. The reaction mixture was cooled to room temperature, and extracted with ammonium chloride aqueous solution (500 mL) and ethyl acetate (500 mL x 3). The organic phases were combined and washed with saturated brine (500 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 100 / 1, v / v) to give compound 64-2. 1H NMR (400MHz, DMSO-d6): δ8.10(d,J=5.2Hz,1H),7.60(d,J=3.6Hz,1H),7.37(d, J=5.2Hz,1H),6.60(d,J=3.6Hz,1H),1.90-1.83(m,3H),1.05(d,J=6.8Hz,18H).

[0605] Step 2

[0606] Compound 64-2 (5.00 g, 14.2 mmol) was dissolved in tetrahydrofuran (50 mL). Under a nitrogen atmosphere, n-butyllithium (11.3 mL, 28.3 mmol, 2.5 mol / L n-hexane solution) was slowly added dropwise at -78 °C, and the mixture was stirred at -78 °C for 0.5 h. N-fluorobis(benzenesulfonamide) (4.91 g, 15.6 mmol) was added, and the mixture was stirred at 25 °C for 1 h. The reaction mixture was extracted with ammonium chloride aqueous solution (100 mL) and ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 100 / 1, v / v) to obtain compound 64-3. 1 H NMR (400MHz, CDCl3): δ8.18 (dd, J=8.4, 5.2Hz, 1H), 7.26 (d, J=3.6Hz, 1H), 6.76 (dd, J=9.6,5.2Hz,1H),6.63(d,J=3.6Hz,1H),1.89-1.81(m,3H),1.12(d,J=6.8Hz,18H).

[0607] Step 3

[0608] Compound 64-3 (2.30 g, 7.86 mmol) was dissolved in tetrahydrofuran (50 mL). Under a nitrogen atmosphere, sec-butyllithium (13.3 mL, 17.3 mmol, 1.3 mol / L n-hexane solution) was slowly added dropwise at -78 °C, and the mixture was stirred at -78 °C for 1 hour. (1R)-(-)-10-camphorsulfonazine (4.51 g, 19.7 mmol) was added, and the mixture was stirred at 25 °C for 1 hour. The reaction mixture was added dropwise to an aqueous ammonium chloride solution (50 mL), extracted with ethyl acetate (50 mL x 3), and the organic phases were combined and washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 20 / 1, v / v) to give compound 64-4. 1¹H NMR (400MHz, CDCl₃): δ 8.06 (d, J = 12.0Hz, 1H), 7.23 (d, J = 4.0Hz, 1H), 6.56 (d, J = 4.0Hz, 1H), 4.89 (s, 1H), 1.87–1.76 (m, 3H), 1.11 (d, J = 6.8Hz, 18H). ESI-MS theoretical calculation: [M+H] + =309.17, measured value 309.0.

[0609] Step 4

[0610] Compound 64-4 (1.20 g, 3.89 mmol) and triphenylphosphine (1.33 g, 5.06 mmol) were dissolved in tetrahydrofuran (40 mL). Diisopropyl azodicarbonate (1.02 g, 5.06 mmol) was slowly added dropwise at 0 °C under a nitrogen atmosphere and stirred at 0 °C for 0.5 h. Methanol (1.17 g, 36.6 mmol) was added, and the mixture was stirred at 25 °C for 1 h. The reaction mixture was added dropwise to an ammonium chloride aqueous solution (50 mL), extracted with ethyl acetate (50 mL x 3), and the organic phases were combined and washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 0, v / v) to give compound 64-5. ESI-MS theoretical calculation: [M+H] + =323.19, measured value 323.0.

[0611] Step 5

[0612] Compound 64-5 (800 mg, 2.48 mmol) was dissolved in tetrahydrofuran (20 mL). Tetrabutylammonium fluoride (4.96 mL, 17.3 mmol, 1.0 mol / L tetrahydrofuran solution) was slowly added dropwise under a nitrogen atmosphere at 0 °C, and the mixture was stirred at 25 °C for 1.5 hours. The reaction mixture was then extracted with water (50 mL) and ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 1, v / v) to give compound 64-6. 1 ¹H NMR (400MHz, DMSO-d⁶): δ 11.80 (s, 1H), 8.18 (d, J = 12.0Hz, 1H), 7.49–7.47 (m, 1H), 6.47–6.45 (m, 1H), 3.91 (s, 3H). ESI-MS theoretical calculation: [M+H] + =167.05, measured value 167.0.

[0613] Step 6

[0614] Compound 64-6 (3.80 g, 22.9 mmol) was dissolved in N,N-dimethylformamide (50 mL). Under a nitrogen atmosphere, N-bromosuccinimide (4.07 g, 22.9 mmol) was slowly added at 0 °C, and the mixture was stirred at 25 °C for 1 hour. The reaction solution was extracted with 50 mL of sodium bicarbonate aqueous solution and ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / dichloromethane, 1 / 1, v / v) to give compound 64-7. 1 H NMR (400MHz, DMSO-d6): δ12.18 (s, 1H), 8.26 (d, J = 9.6 Hz, 1H), 7.69 (d, J = 2.8 Hz, 1H), 3.93 (s, 3H).

[0615] Step 7

[0616] Compound 64-7 (5.16 g, 21.1 mmol) was dissolved in dichloromethane (60 mL). Under a nitrogen atmosphere, N,N-diisopropylethylamine (4.08 g, 31.6 mmol), di-tert-butyl dicarbonate (6.89 g, 31.6 mmol), and 4-dimethylaminopyridine (772 mg, 6.32 mmol) were slowly added at 0 °C, and the mixture was stirred at 25 °C for 2 hours. The reaction mixture was then extracted with water (50 mL) and dichloromethane (100 mL x 3). The combined organic phases were washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / dichloromethane, 5 / 1, v / v) to give compound 64-8. 1 H NMR (400MHz, DMSO-d6): δ8.41 (d, J=9.6Hz, 1H), 7.97 (s, 1H), 3.98 (s, 3H), 1.60 (s, 9H).

[0617] Step 8

[0618] In a nitrogen-filled glove box, compound 64-8 (304 mg, 0.88 mmol), (2R)-2-(bromomethyl)azacyclobutane-1-carboxylic acid tert-butyl ester (220 mg, 0.88 mmol), anhydrous sodium carbonate (187 mg, 1.76 mmol), tris(trimethylsilyl)silane (219 mg, 0.88 mmol), nickel chloride dimethoxyethane (9.67 mg, 0.044 mmol), 4,4'-di-tert-butyl-2,2'-dipyridine (11.8 mg, 0.044 mmol), and bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium di(hexafluorophosphate) (9.87 mg, 0.0088 mmol) were dissolved in ethylene glycol dimethyl ether (4 mL). The reaction mixture was irradiated with a 34W blue LED (420nm) at 25°C and stirred for 16 hours. After the reaction was complete, the blue light was turned off, and the reaction mixture was extracted with water (20mL) and ethyl acetate (20mL x 3). The organic phases were combined and washed with saturated brine (20mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 1, v / v) to give compound 64-9. ESI-MS theoretical calculation: [M+H] + =436.22, measured value 436.1.

[0619] Step 9

[0620] Compound 64-9 (350 mg, 0.80 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (0.6 mL) was slowly added at 0 °C. The mixture was stirred at 25 °C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was extracted with saturated sodium bicarbonate aqueous solution (20 mL) and dichloromethane (20 mL x 3). The organic phases were combined and washed with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 64-10. ESI-MS theoretical value: [M+H] + =236.11, measured value: 236.0.

[0621] Step 10

[0622] Compound 64-10 (110 mg, 0.55 mmol) was dissolved in methanol (2 mL), and N,N-diisopropylethylamine (180 mg, 1.41 mmol) and 37% formaldehyde aqueous solution (15.5 mg, 0.52 mmol) were added. The mixture was stirred at 25 °C for 0.5 h. Sodium cyanoborohydride (29.8 mg, 0.47 mmol) was added, and the mixture was stirred at 25 °C for 2 h. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product containing the target compound. Compound 64 was purified by high performance liquid chromatography (Waters-SunFire-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 10-40%, retention time: 8.4-9.8 min, run time: 17 min) to obtain compound 64. 1 ¹H NMR (400MHz, DMSO-d⁶): δ 11.47 (s, 1H), 8.13 (d, J = 9.6Hz, 1H), 7.22 (s, 1H), 3.90 (s, 3H), 3.22–3.19 (m, 1H), 3.12–3.07 (m, 1H), 2.93–2.89 (m, 1H), 2.79–2.74 (m, 1H), 2.59–2.56 (m, 1H), 2.09 (s, 3H), 1.92–1.86 (m, 1H), 1.78–1.72 (m, 1H). ESI-MS theoretical calculation: [M+H] + =250.13, measured value 250.0.

[0623] Example 65

[0624] Synthesis route:

[0625] first step

[0626] Compound 8-1 (5.00 g, 33.8 mmol) was dissolved in N,N-dimethylformamide (40 mL). Under a nitrogen atmosphere, N-bromosuccinimide (6.55 g, 36.8 mmol) was slowly added at 0 °C, and the mixture was stirred at 0 °C for 2 hours. The reaction mixture was extracted with water (100 mL) and ethyl acetate (150 mL x 3). The combined organic phases were washed with saturated brine (150 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / dichloromethane, 1 / 1, v / v) to give compound 65-1. 1 H NMR (400MHz, DMSO-d6): δ11.96 (s, 1H), 8.07 (d, J = 4.0 Hz, 1H), 7.69 (d, J = 4.0 Hz, 1H), 7.36 (s, 1H), 3.89 (s, 3H).

[0627] Step 2

[0628] Compound 65-1 (6.27 g, 27.6 mmol) was dissolved in dichloromethane (90 mL). Under a nitrogen atmosphere, N,N-diisopropylethylamine (7.13 g, 55.2 mmol), di-tert-butyl dicarbonate (9.03 g, 41.4 mmol), and 4-dimethylaminopyridine (340 mg, 2.76 mmol) were slowly added at 0 °C, and the mixture was stirred at 25 °C for 2 hours. The reaction mixture was extracted with saturated ammonium chloride aqueous solution (100 mL) and dichloromethane (100 mL x 3). The organic phases were combined and washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / dichloromethane, 1 / 1, v / v) to obtain compound 65-2. 1 H NMR (400MHz, DMSO-d6): δ8.18 (d, J = 4.0 Hz, 1H), 7.98 (d, J = 4.00 Hz, 1H), 7.40 (s, 1H), 3.90 (s, 3H), 1.60 (s, 9H).

[0629] Step 3

[0630] Compound 65-3 (1.70 g, 7.90 mmol) was dissolved in isopropyl acetate (5 mL). Sodium borohydride (480 mg, 12.6 mmol) and boron trifluoride diethyl ether (2.24 g, 15.8 mmol) were added under a nitrogen atmosphere at 0 °C, and the mixture was stirred at 0 °C for 3 hours. A 0.5 mol / L sodium hydroxide aqueous solution (12 mL) was added to the reaction mixture, and the mixture was stirred at 50 °C for 0.5 hours. The reaction mixture was cooled to room temperature, extracted with ethyl acetate (50 mL x 3), and the combined organic phases were washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 65-4. 1 HNMR (400MHz, DMSO-d6): δ4.11-4.06(m,1H),3.87-3.71(m,1H),3.66-3.61(m, 2H), 3.27-3.21 (m, 1H), 2.73-2.62 (m, 1H), 1.36 (s, 9H), 1.13 (d, J = 7.2Hz, 3H).

[0631] Step 4

[0632] Compound 65-4 (1.20 g, 5.96 mmol) was dissolved in acetonitrile (12 mL). Under a nitrogen atmosphere, triphenylphosphine (1.72 g, 6.56 mmol) was added, followed by dropwise addition of carbon tetrabromide (2.17 g, 6.56 mmol) in acetonitrile (4 mL) at 0 °C. The mixture was stirred at 25 °C for 12 hours. The reaction solution was extracted with saturated ammonium chloride aqueous solution (50 mL) and dichloromethane (50 mL x 3). The organic phases were combined and washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1, v / v) to obtain compound 65-5. 1 H NMR (400MHz, CDCl3): δ4.45-4.39(m,1H),3.97-3.92(m,1H),3.71-3.65(m,1H),3.48- 3.43(m,1H),3.34-3.31(m,1H),2.79-2.71(m,1H),1.44(s,9H),1.27(d,J=7.2Hz,3H).

[0633] Step 5

[0634] In a nitrogen-filled glove box, compounds 65-2 (203 mg, 0.62 mmol), 65-5 (163 mg, 0.62 mmol), anhydrous sodium carbonate (131 mg, 1.24 mmol), tris(trimethylsilyl)silane (154 mg, 0.62 mmol), nickel chloride dimethoxyethane (6.81 mg, 0.031 mmol), 4,4'-di-tert-butyl-2,2'-dipyridine (8.32 mg, 0.031 mmol), and bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium di(hexafluorophosphate) (6.96 mg, 0.0062 mmol) were dissolved in ethylene glycol dimethyl ether (4 mL). The reaction mixture was irradiated with a 34 W blue LED (420 nm) and stirred at 25 °C for 16 hours. After the reaction was complete, the blue light was turned off, and the reaction solution was extracted with water (20 mL) and ethyl acetate (20 mL x 3). The organic phases were combined and washed with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 1, v / v) to give compound 64-6. ESI-MS theoretical calculation: [M+H] + =432.24, measured value 432.2.

[0635] Step 6

[0636] Compound 65-6 (680 mg, 1.58 mmol) was dissolved in tetrahydrofuran (5 mL), ethanol (5 mL), and water (2 mL). Lithium hydroxide monohydrate (331 mg, 7.90 mmol) was added, and the reaction mixture was stirred at 25 °C for 2 hours. The mixture was then extracted with water (20 mL) and ethyl acetate (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane / methanol, 20 / 1, v / v) to obtain compound 65-7. 1 ¹H NMR (400MHz, DMSO-d⁶): δ 11.22 (s, 1H), 7.94 (d, J = 2.8Hz, 1H), 7.49 (d, J = 2.8Hz, 1H), 7.19 (s 1H), 4.56–4.50 (m, 1H), 3.92–3.88 (m, 1H), 3.82 (s, 3H), 3.32–3.30 (m, 1H), 3.11–3.03 (m, 2H), 2.69–2.64 (m, 1H), 1.35 (s, 9H), 1.08 (d, J = 7.2Hz, 3H). ESI-MS theoretical calculation: [M+H] + =332.19, measured value 332.1.

[0637] Step 7

[0638] Compound 65-7 (215 mg, 0.65 mmol) was dissolved in tetrahydrofuran (5 mL), and a tetrahydrofuran solution of lithium aluminum hydride (2.6 mL, 6.50 mmol, 2.5 mol / L) was slowly added dropwise at 0 °C. The reaction mixture was stirred at 60 °C for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and quenched with ice water (0.3 mL). Then, 15% sodium hydroxide aqueous solution (0.3 mL) and water (0.9 mL) were added. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product containing the target compound. Compound 65 was purified by high performance liquid chromatography (Waters-SunFire-C18-10 μm-19*250 mm, mobile phase: acetonitrile-0.05% ammonia, gradient: 13-23%, retention time: 9.0-11.0 min, run time: 16 min) to obtain compound 65. 1 ¹H NMR (400MHz, CD₃OD): δ 7.93 (d, J = 2.8Hz, 1H), 7.61 (d, J = 2.8Hz, 1H), 7.20 (s, 1H), 3.90 (s, 3H), 3.69–2.66 (m, 1H), 3.15–3.13 (m, 2H), 2.97–2.94 (m, 2H), 2.60–2.54 (m, 1H), 2.19 (s, 3H), 1.28 (d, J = 7.2Hz, 3H). ESI-MS theoretical calculation: [M+H] +=246.15, measured value 246.0.

[0639] Example 66

[0640] Synthesis route:

[0641] first step

[0642] Compound 66-1 (25.0 g, 133 mmol) was dissolved in dichloromethane (250 mL). Under a nitrogen atmosphere, imidazole (27.2 g, 399 mmol) and tert-butyldimethylchlorosilane (26.1 g, 173 mmol) were added at 0 °C, and the mixture was stirred at 25 °C for 12 hours. The reaction mixture was extracted with saturated ammonium chloride aqueous solution (200 mL) and dichloromethane (200 mL). The organic phases were combined and washed with saturated brine (200 mL x 3). The organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1, v / v) to give compound 66-2. 1 H NMR (400MHz, CDCl3): δ8.26-8.25(m,1H),7.86-7.84(m,1H),7.32-7.29(m,1H),4.69(s,2H),0.96(s,9H),0.14(s,6H).

[0643] Step 2

[0644] Compound 66-2 (5.00 g, 16.5 mmol) was dissolved in N,N-dimethylformamide (35 mL). Under a nitrogen atmosphere, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (1.21 g, 1.65 mmol), benzyl alcohol (8.94 g, 82.7 mmol), and triethylamine (8.37 g, 82.7 mmol) were added. The mixture was purged three times with carbon monoxide and stirred at 100 °C for 12 hours under a carbon monoxide atmosphere. The reaction mixture was extracted with water (150 mL) and ethyl acetate (150 mL x 3). The organic phases were combined and washed with saturated brine (150 mL x 3). The organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1, v / v) to obtain compound 66-3. 1 ¹H NMR (400MHz, CDCl₃): δ 8.64–8.61 (m, 1H), 8.19 (d, J = 8.0Hz, 1H), 7.51–7.48 (m, 2H), 7.37–7.32 (m, 4H), 5.44 (s, 2H), 5.07 (s, 2H), 0.95 (s, 9H), 0.10 (s, 6H). ESI-MS theoretical calculation: [M+H] +=358.18, measured value 358.0.

[0645] Step 3

[0646] Compound 66-3 (6.00 g, 16.8 mmol) was dissolved in ethyl acetate (80 mL). Under an argon atmosphere, 10% wet palladium / carbon (700 mg) was added, and the mixture was purged three times with hydrogen. The mixture was stirred at 25 °C for 12 hours under a hydrogen atmosphere. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate (50 mL x 3). The filtrate was concentrated under reduced pressure to obtain compound 66-4. ESI-MS theoretical value: [M+H] + =268.13, measured value 268.0.

[0647] Step 4

[0648] Compound 66-4 (4.40 g, 16.5 mmol) was dissolved in dichloromethane (50 mL). Under a nitrogen atmosphere, diisopropylethylamine (7.44 g, 57.6 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (7.82 g, 20.6 mmol), and compound 65-5 (2.62 g, 15.6 mmol) were added, and the mixture was stirred at 25 °C for 2 hours. The reaction mixture was extracted with water (100 mL) and dichloromethane (50 mL x 3). The organic phases were combined and washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 20 / 1, v / v) to give compound 66-6. 1 ¹H NMR (400MHz, CDCl₃): δ 8.72–8.69 (m, 1H), 8.48–8.46 (m, 1H), 8.27–8.25 (m, 1H), 7.47 (dd, J = 8.0, 4.4Hz, 1H), 5.28 (s, 2H), 4.64 (dd, J = 9.2, 5.6Hz, 1H), 3.76 (s, 3H), 2.33–2.23 (m, 1H), 1.02 (d, J = 6.8Hz, 6H), 0.96 (s, 9H), 0.13 (s, 6H). ESI-MS theoretical calculation: [M+H] + =381.21, measured value 381.1.

[0649] Step 5

[0650] Compound 66-6 (600 mg, 1.58 mmol) was dissolved in toluene (15 mL). Under a nitrogen atmosphere, iodophenyldiacetic acid (1.27 g, 3.95 mmol), palladium acetate (17.7 mg, 0.079 mmol), and glacial acetic acid (200 mg, 3.33 mmol) were added, and the mixture was stirred at 110 °C for 2 hours in a microwave reactor. The reaction solution was cooled to room temperature, and water (20 mL) and ethyl acetate (20 mL x 3) were added for extraction. The organic phases were combined and washed with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1, v / v) to give compound 66-7. ESI-MS theoretical value: [M+H] + =379.20, measured value 379.1.

[0651] Step 6

[0652] Compound 66-7 (2.60 g, 6.87 mmol) was dissolved in dichloromethane (20 mL), and a dioxane solution of hydrochloric acid (20 mL, 80.0 mmol, 4.0 mol / L) was added. The mixture was stirred at 25 °C for 2 hours. The reaction solution was concentrated under reduced pressure to give the monohydrochloride salt of compound 66-8. ESI-MS theoretical calculation: [M+H] + =130.08, measured value 130.1.

[0653] Step 7

[0654] The monohydrochloride salt (1.40 g, 8.45 mmol) of compound 66-8 was dissolved in tetrahydrofuran (8 mL) and water (2 mL), and sodium carbonate (4.60 g, 43.4 mmol) and di-tert-butyl dicarbonate (4.73 g, 21.7 mmol) were added. The mixture was stirred at 25 °C for 4 hours. The reaction solution was extracted with water (30 mL) and ethyl acetate (60 mL x 3). The organic phases were combined and washed with saturated brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1, v / v) to give compound 66-9. 1 HNMR (400MHz, CDCl3): δ4.18 (d, J=4.8Hz, 1H), 4.10 (t, J=8.0Hz, 1H), 3.76 (s, 3H), 3.44(dd,J=8.0,5.2Hz,1H),2.56-2.45(m,1H),1.42(s,9H),1.32(d,J=6.8Hz,3H).

[0655] Step 8

[0656] Compound 66-9 (1.40 g, 6.11 mmol) was dissolved in methanol (20 mL). Sodium borohydride (2.31 g, 61.1 mmol) was added in portions at 0 °C under a nitrogen atmosphere. The mixture was stirred at 0 °C for 1 hour and then at 25 °C for 3 hours. The reaction mixture was extracted with water (100 mL) and ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 4 / 1, v / v) to give compound 66-10. 1 H NMR (400MHz, CDCl3): δ4.00-3.96 (m, 1H), 3.88 (t, J = 8.4Hz, 1H), 3.76-3.67 (m, 2H), 3.44(dd,J=8.4,6.8Hz,1H),2.35-2.25(m,1H),1.45(s,9H),1.18(d,J=6.8Hz,3H).

[0657] Step 9

[0658] Compound 66-10 (1.10 g, 5.47 mmol) was dissolved in acetonitrile (12 mL). Under a nitrogen atmosphere, triphenylphosphine (1.58 g, 6.02 mmol) was added, followed by dropwise addition of carbon tetrabromide (2.00 g, 6.02 mmol) in acetonitrile (4 mL) at 0 °C. The mixture was stirred at 25 °C for 12 hours. The reaction solution was extracted with saturated ammonium chloride aqueous solution (50 mL) and dichloromethane (50 mL x 3). The organic phases were combined and washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 20 / 1, v / v) to obtain compound 66-11. 1 H NMR (400MHz, CDCl3): δ3.94-3.89(m,2H),3.69(dd,J=9.6,3.2Hz,1H),3.52(dd,J=9.6,8.4 Hz, 1H), 3.35 (dd, J = 8.0, 5.6Hz, 1H), 2.46-2.36 (m, 1H), 1.44 (s, 9H), 1.25 (d, J = 6.8Hz, 3H).

[0659] Step 10

[0660] In a nitrogen-filled glove box, compounds 65-2 (203 mg, 0.62 mmol), 66-11 (163 mg, 0.62 mmol), anhydrous sodium carbonate (131 mg, 1.24 mmol), tris(trimethylsilyl)silane (154 mg, 0.62 mmol), nickel chloride dimethoxyethane (6.81 mg, 0.031 mmol), 4,4'-di-tert-butyl-2,2'-dipyridine (8.32 mg, 0.031 mmol), and bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium di(hexafluorophosphate) (6.96 mg, 0.0062 mmol) were dissolved in ethylene glycol dimethyl ether (4 mL). The reaction mixture was irradiated with a 34 W blue LED (420 nm) and stirred at 25 °C for 16 hours. After the reaction was complete, the blue light was turned off, and the reaction solution was extracted with water (20 mL) and ethyl acetate (20 mL x 3). The organic phases were combined and washed with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 1, v / v) to give compound 66-12. ESI-MS theoretical calculation: [M+H] + =432.24, measured value 432.1.

[0661] Step 11

[0662] Compound 66-12 (580 mg, 1.34 mmol) was dissolved in tetrahydrofuran (5 mL), ethanol (5 mL), and water (2 mL). Lithium hydroxide monohydrate (281 mg, 6.70 mmol) was added, and the reaction mixture was stirred at 25 °C for 2 hours. The mixture was then extracted with water (20 mL) and ethyl acetate (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane / methanol, 20 / 1, v / v) to give compound 66-13. ESI-MS theoretical value: [M+H] + =332.19, measured value 332.1.

[0663] Step Twelve

[0664] Compound 66-13 (150 mg, 0.45 mmol) was dissolved in tetrahydrofuran (5 mL), and a tetrahydrofuran solution of lithium aluminum hydride (1.8 mL, 4.50 mmol, 2.5 mol / L) was slowly added dropwise at 0 °C. The reaction mixture was stirred at 60 °C for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and quenched with ice water (0.18 mL). Then, 15% sodium hydroxide aqueous solution (0.18 mL) and water (0.54 mL) were added. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product containing the target compound. Compound 66 was purified by high performance liquid chromatography (Waters-SunFire-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 13-38%, retention time: 8.2-10.0 min, run time: 16 min) to obtain compound 66. 1 ¹H NMR (400MHz, DMSO-d⁶): δ 11.16 (s, 1H), 7.92 (d, J = 2.8Hz, 1H), 7.51 (d, J = 2.8Hz, 1H), 7.21 (s, 1H), 3.82 (s, 3H), 3.41 (t, J = 6.4Hz, 1H), 2.86–2.82 (m, 1H), 2.78–2.73 (m, 1H), 2.71–2.67 (m, 1H), 2.24–2.21 (m, 1H), 2.13–2.06 (m, 4H), 0.81 (d, J = 6.8Hz, 3H). ESI-MS theoretical calculation: [M+H] + =246.15, measured value 246.0.

[0665] Example 67

[0666] Synthesis route:

[0667] Compound 8 (100 mg, 0.432 mmol) was dissolved in dichloromethane (5 mL), and a dichloromethane solution of boron tribromide (2.16 mL, 2.16 mmol, 1.0 mol / L) was slowly added dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 2 hours under a nitrogen atmosphere. The reaction mixture was then cooled to 0 °C, quenched by slow addition of methanol (5 mL), and stirred at 25 °C for 0.5 hours. The mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane / methanol, 10 / 1, v / v) to obtain compound 67. 11¹H NMR (400MHz, DMSO-d⁶): δ 11.31 (s, 1H), 9.86 (s, 1H), 7.88 (d, J = 2.8Hz, 1H), 7.41 (d, J = 2.8Hz, 1H), 7.30 (d, J = 2.0Hz, 1H), 4.48–4.44 (m, 1H), 4.02–3.98 (m, 1H), 3.80–3.76 (m, 1H), 3.26–3.22 (m, 1H), 3.10–3.06 (m, 1H), 2.64 (s, 3H), 2.39–2.31 (m, 1H), 2.30–2.23 (m, 1H). ESI-MS theoretical calculation: [M+H] + =218.12, measured value 218.0.

[0668] Example 68

[0669] Structural formula:

[0670] Referring to the synthetic route and method of Example 8, by replacing (R)-N-carboxylic acid tert-butyl ester-azacyclobutane-2-carboxylic acid with (S)-N-carboxylic acid tert-butyl ester-azacyclobutane-2-carboxylic acid, compound 68 can be prepared. 1 ¹H NMR (400MHz, DMSO-d⁶): δ 11.17 (s, 1H), 7.92 (d, J = 2.8Hz, 1H), 7.50 (d, J = 2.8Hz, 1H), 7.19 (d, J = 2.0Hz, 1H), 3.81 (s, 3H), 3.28–3.25 (m, 1H), 3.24–3.20 (m, 1H), 2.91–2.85 (m, 1H), 2.81–2.74 (m, 1H), 2.72–2.69 (m, 1H), 2.13 (s, 3H), 1.98–1.93 (m, 1H), 1.87–1.79 (m, 1H). ESI-MS theoretical calculation: [M+H] + =232.14, measured value 232.0.

[0671] Example 69

[0672] Structural formula:

[0673] Referring to the synthetic route and method of Example 11, by replacing (R)-N-carboxylic acid tert-butyl ester-azacyclobutane-2-carboxylic acid with (S)-N-carboxylic acid tert-butyl ester-azacyclobutane-2-carboxylic acid, compound 69 can be prepared. 1¹H NMR (400MHz, DMSO-d⁶): δ 10.58 (s, 1H), 7.06–7.02 (m, 2H), 6.56 (d, J = 8.4 Hz, 1H), 4.51 (t, J = 8.8 Hz, 2H), 3.48–3.44 (m, 2H), 3.26–3.18 (m, 1H), 3.12–3.03 (m, 1H), 2.97–2.93 (m, 1H), 2.73–2.65 (m, 1H), 2.60–2.54 (m, 1H), 2.12 (s, 3H), 1.96–1.89 (m, 1H), 1.83–1.75 (m, 1H). ESI-MS theoretical calculation: [M+H] + =243.14, measured value 243.0.

[0674] Example 70

[0675] Structural formula:

[0676] Referring to the synthetic route and method of Example 14, by replacing (2R)-2-(bromomethyl)azacyclobutane-1-carboxylic acid tert-butyl ester with (2S)-2-(bromomethyl)azacyclobutane-1-carboxylic acid tert-butyl ester, compound 70 can be prepared. 1 ¹H NMR (400MHz, DMSO-d⁶): δ 12.50 (s, 1H), 7.34 (d, J = 8.8 Hz, 1H), 7.13 (s, 1H), 6.95 (dd, J = 8.8, 2.0 Hz, 1H), 3.78 (s, 3H), 3.25–3.20 (m, 2H), 3.08–3.03 (m, 1H), 2.99–2.96 (m, 1H), 2.61–2.53 (m, 1H), 2.10 (s, 3H), 1.90–1.75 (m, 2H). ESI-MS theoretical calculation: [M+H] + =232.14, measured value 232.0.

[0677] Example 71

[0678] Structural formula:

[0679] Following the synthetic routes and methods of Examples 3 and 37, by replacing (2R)-2-(bromomethyl)azacyclobutane-1-carboxylic acid tert-butyl ester with (2S)-2-(bromomethyl)azacyclobutane-1-carboxylic acid tert-butyl ester, compound 71 can be prepared. 1H NMR (400MHz, DMSO-d6): δ 10.87 (s, 1H), 7.31–7.24 (m, 2H), 7.18 (s, 1H), 6.90–6.86 (m, 1H), 4.34 (s, 1H), 3.28–3.22 (m, 4H), 2.93–2.89 (m, 1H), 2.78–2.62 (m, 2H), 2.58–2.53 (m, 1H), 2.34–2.25 (m, 1H), 1.96–1.87 (m, 1H), 1.83–1.73 (m, 1H). ESI-MS theoretical calculation: [M+H]+ = 249.13, measured value 249.0.

[0680] Effects Example 1: Compound on 5-HT 2A Evaluation of receptor calcium flux agonist activity

[0681] Experimental objective:

[0682] Using expression of human 5-HT 2A The effect of the compound on 5-HT was measured in a stable cell line (HEK293 cells) of the receptor. 2A Receptor activity.

[0683] The experimental reagents and consumables are shown in Table 1:

[0684] Table 1

[0685] The experimental instruments are shown in Table 2:

[0686] Table 2

[0687] Experimental procedure:

[0688] Day 1: Cell inoculation and compound preparation

[0689] The test compound was diluted with DMSO to a stock solution at a concentration 400 times higher than the highest concentration tested on the 384-well LDV plate. The compound solution was then transferred to the 384-well plate.

[0690] HEK-293 / 5-HT was cultured in DMEM medium (10% FBS). 2A Cells were separated using 0.25% Trypsin-EDTA when the cell density reached 80%.

[0691] Cell density was measured and cells were diluted using DMEM (10% FBS).

[0692] Using Multidrop, 30 μL of cells (25,000 cells per well) were added to each well of a Matrigel-coated 384-well plate and incubated at 37°C and 5% CO2 for 20–24 hours.

[0693] Day 2: Basic Cell Experiment Procedures

[0694] Remove the culture medium from the cell plate and add 40 μL of fluorescent dye (AAT bioquest (catalog number: 21080)) to each well of the cell plate. Incubate at 37°C in the dark with 5% CO2 for 0.5 hours.

[0695] Add 20 μL of experimental buffer (1X HBSS + 20 mM HEPES + 0.1% BSA) to each well in the compound plate to prepare a 5-fold concentration of the agonist working solution for calcium signal reading. Program 10 μL of the compound to be added to the cell plate (10 μL + 40 μL) to collect activation data.

[0696] Use FLIPR to read and save data at room temperature with the specified settings.

[0697] Data Analysis:

[0698] Compound dilutions were prepared from 20 mmol dimethyl sulfoxide (DMSO) stock solution. Compounds were added to a fluorescence imaging flatbed reader, and fluorescence changes reflecting calcium ion release were monitored every 1 second for a total of 130 seconds (excitation wavelength = 470–495 nm, emission wavelength = 515–575 nm). Data were derived as the difference between maximum and minimum fluorescence for each well. The relative EC was determined using nonlinear regression calculations. 50 And Emax value (using XL-fit and Graphpad Prism software).

[0699] The experimental results are shown in Table 3:

[0700] Table 3

[0701] Published compound structures:

[0702] Experimental conclusion:

[0703] The experimental samples (compounds) were prepared according to the corresponding examples, and the results are shown in the table above. In this experimental system, the compounds of this application showed efficacy against 5-HT. 2AThe receptor exhibits agonistic activity.

[0704] Effects Example 2: Compound on 5-HT 2B Evaluation of receptor calcium flux agonist activity

[0705] Experimental objective:

[0706] Using expression of human 5-HT 2B The effect of the compound on 5-HT was measured in a stable cell line (HEK293 cells) of the receptor. 2B Receptor activity.

[0707] The experimental reagents and consumables are shown in Table 4:

[0708] Table 4

[0709] The experimental instruments are shown in Table 5:

[0710] Table 5

[0711] Experimental procedure:

[0712] Day 1: Cell inoculation and compound preparation

[0713] The test compound was diluted with DMSO to a stock solution at a concentration 400 times higher than the highest concentration tested on the 384-well LDV plate. The compound solution was then transferred to the 384-well plate.

[0714] HEK-293 / 5-HT was cultured in DMEM medium (10% FBS). 2b Cells were separated using 0.25% Trypsin-EDTA when the cell density reached 80%.

[0715] Cell density was measured and cells were diluted using DMEM (10% FBS).

[0716] Using Multidrop, 30 μL of cells (25,000 cells per well) were added to each well of a Matrigel-coated 384-well plate and incubated at 37°C and 5% CO2 for 20–24 hours.

[0717] Day 2: Basic Cell Experiment Procedures

[0718] Remove the culture medium from the cell plate and add 40 μL of fluorescent dye (AAT bioquest (catalog number: 21080)) to each well of the cell plate. Incubate at 37°C in the dark with 5% CO2 for 0.5 hours.

[0719] Add 20 μL of experimental buffer (1X HBSS + 20 mM HEPES + 0.1% BSA) to each well in the compound plate to prepare a 5-fold concentration of the agonist working solution for calcium signal reading. The instrument program adds 10 μL of the compound to the cell plate (10 μL + 40 μL) to collect activation data.

[0720] Use FLIPR to read and save data at room temperature with the specified settings.

[0721] Data Analysis:

[0722] Compound dilutions were prepared from 20 mmol dimethyl sulfoxide (DMSO) stock solution. Compounds were added to a fluorescence imaging flatbed reader, and fluorescence changes reflecting calcium ion release were monitored every 1 second for a total of 130 seconds (excitation wavelength = 470–495 nm, emission wavelength = 515–575 nm). Data were derived as the difference between maximum and minimum fluorescence for each well. The relative EC was determined using nonlinear regression calculations. 50 And Emax value (using XL-fit and Graphpad Prism software).

[0723] The experimental results are shown in Table 6:

[0724] Table 6

[0725] Published compound structures:

[0726] " / " indicates that there is no corresponding value.

[0727] Experimental conclusion:

[0728] The experimental samples (compounds) were prepared according to the corresponding examples, and the results are shown in the table above. In this experimental system, the compounds of this application showed efficacy against 5-HT. 2B The receptor showed no agonistic activity.

[0729] Effects of Compound 3 on 5-HT 2C Evaluation of receptor calcium flux agonist activity

[0730] Experimental objective:

[0731] Using expression of human 5-HT 2C The effect of the compound on 5-HT was measured in a stable cell line (HEK293 cells) of the receptor. 2C Receptor activity.

[0732] The experimental reagents and consumables are shown in Table 7:

[0733] Table 7

[0734] The experimental instruments are shown in Table 8:

[0735] Table 8

[0736] Experimental procedure:

[0737] Day 1: Cell inoculation and compound preparation

[0738] The test compound was diluted with DMSO to a stock solution at a concentration 400 times higher than the highest concentration tested on the 384-well LDV plate. The compound solution was then transferred to the 384-well plate.

[0739] HEK-293 / 5-HT was cultured in DMEM medium (10% FBS). 2C Cells were separated using 0.25% Trypsin-EDTA when the cell density reached 80%.

[0740] Cell density was measured and cells were diluted using DMEM (10% FBS).

[0741] Using Multidrop, 30 μL of cells (25,000 cells per well) were added to each well of a Matrigel-coated 384-well plate and incubated at 37°C and 5% CO2 for 20–24 hours.

[0742] Day 2: Basic Cell Experiment Procedures

[0743] Remove the culture medium from the cell plate and add 40 μL of fluorescent dye (AAT bioquest (catalog number: 21080)) to each well of the cell plate. Incubate at 37°C in the dark with 5% CO2 for 0.5 hours.

[0744] Add 20 μL of experimental buffer (1X HBSS + 20 mM HEPES + 0.1% BSA) to each well in the compound plate to prepare a 5-fold concentration of the agonist working solution for calcium signal reading. The instrument program adds 10 μL of the compound to the cell plate (10 μL + 40 μL) to collect activation data.

[0745] Use FLIPR to read and save data at room temperature with the specified settings.

[0746] Data Analysis:

[0747] Compound dilutions were prepared from 20 mmol dimethyl sulfoxide (DMSO) stock solution. Compounds were added to a fluorescence imaging flatbed reader, and fluorescence changes reflecting calcium ion release were monitored every 1 second for a total of 130 seconds (excitation wavelength = 470–495 nm, emission wavelength = 515–575 nm). Data were derived as the difference between maximum and minimum fluorescence for each well. The relative EC was determined using nonlinear regression calculations. 50 And Emax value (using XL-fit and Graphpad Prism software).

[0748] The experimental results are shown in Table 9:

[0749] Table 9

[0750] Published compound structures:

[0751] " / " indicates that there is no corresponding value.

[0752] Experimental conclusion:

[0753] The experimental samples (compounds) were prepared according to the corresponding examples, and the results are shown in the table above. In this experimental system, some compounds of this application showed efficacy against 5-HT. 2C The receptor exhibits agonistic activity.

[0754] Effects of Compound 4 on 5-HT 1A Evaluation of receptor calcium flux agonist activity

[0755] Experimental objective:

[0756] Using expression of human 5-HT 1A The receptor's stable cell line (CHO cells) was used to measure the effect of the compound on 5-HT. 1A Receptor agonistic activity.

[0757] The experimental reagents and consumables are shown in Table 10:

[0758] Table 10

[0759] The experimental instruments are shown in Table 11:

[0760] Table 11

[0761] Experimental procedure:

[0762] Day 1: Cell Plating

[0763] CHO / 5-HT cultured using culture medium1A Cells were digested with trypsin when they reached a density of 80-90%, and then the digestion was stopped by adding an appropriate amount of culture medium. The cells were centrifuged at 1000 rpm for 5 minutes at room temperature. After discarding the supernatant, the cells were resuspended in culture medium, and 1 ml was used for cell counting. Cell counts and viability were determined using a cell counter. The cells were then diluted to 1×10⁶ cells / mL with culture medium. 6 Add 20 μL / well of cell suspension to a 384-well cell plate (approximately 20,000 cells / well). Incubate the cells overnight at 37°C with 5% CO2.

[0764] Day 2: FLIPR Experiment

[0765] The compound was serially diluted 3-fold at 10 points using Echo, and 750 nL of the compound was transferred to a compound plate in duplicate.

[0766] Remove the culture medium from the cell plate, add 20 μL of buffer and 20 μL of dye to each well of the cell plate, and incubate at 37°C in the dark with 5% CO2 for 50 minutes, then incubate at room temperature for 10 minutes.

[0767] Add 30 μL of experimental buffer (1×HBSS + 20 mM HEPES + 0.5% BSA) to each well in the compound plate to prepare a 5-fold concentration of the agonist working solution for calcium signal reading. Add 10 μL of the compound to the cell plate (10 μL + 40 μL) via FLIPR to collect activation data.

[0768] Use FLIPR to read and save data at room temperature with the specified settings.

[0769] Data Analysis:

[0770] Compound dilutions were prepared from 20 mmol dimethyl sulfoxide (DMSO) stock solution. Compound additions were performed on a fluorescence imaging flatbed reader, and fluorescence changes reflecting calcium ion release were monitored every 1 second for 60 seconds, followed by every 6 seconds for 30 seconds (excitation wavelength = 470–495 nm, emission wavelength = 515–575 nm). Data were derived as the difference between maximum and minimum fluorescence for each well. The relative EC was determined using nonlinear regression calculations. 50 And the Emax value (using XL-fit or Graphpad Prism software).

[0771] The experimental results are shown in Table 12:

[0772] Table 12 " / " indicates that there is no corresponding value.

[0773] Experimental conclusion:

[0774] The experimental samples (compounds) were prepared according to the corresponding examples, and the results are shown in the table above. In this experimental system, some compounds of this application showed efficacy against 5-HT. 1A The receptor did not show agonistic activity.

[0775] Effects of Compound 5 in Example 5 on 5-HT 2A Receptor affinity evaluation

[0776] Experimental objective:

[0777] The main purpose of this experiment is to demonstrate the affinity of the test sample for human 5-HT2A by detecting radiobinding assay.

[0778] The experimental reagents and consumables are shown in Table 13:

[0779] Table 13

[0780] The experimental instruments are shown in Table 14:

[0781] Table 14

[0782] Experimental procedure:

[0783] The compound was serially diluted 3-fold in 10-site increments, and 1 μL of the compound was transferred to a compound plate in duplicate. 100 μL of 5 μg / well 5-HT was added to each well of the reaction plate. 2A Cell membrane, add 100 μL of 0.5 nM to each well of the reaction plate. 3 H-LSD isotopes. Seal the reaction plate with a sealing film and incubate at room temperature for 1 hour. Immerse the GF / C filter plate in 50 μL of 0.3% PEI soaking buffer for at least 0.5 hours. After incubation, collect the reaction solution onto the GF / C filter plate using a cell collector, rinse four times with cold wash buffer, and dry in a 50°C oven for 1 hour. Seal the bottom of the dried GF / C filter plate with a sealing film, add 50 μL of scintillation buffer to each well, and seal. Read using a Microbeta2.

[0784] Data Analysis:

[0785] The percentage of activity was calculated using Microsoft Excel software. The formula is: % Inhibition Rate = (1 - (Sample Well Signal - Average High Control Signal) / (Average Low Control Signal - Average High Control Signal)) × 100

[0786] The IC of each tested sample was calculated using the XLfitXL-FIT four-parameter fitting model. 50 Value and Ki value.

[0787] The experimental results are shown in Table 15:

[0788] Table 15

[0789] Published compound structures:

[0790] Experimental conclusion:

[0791] The experimental samples (compounds) were prepared according to the corresponding examples, and the results are shown in the table above. In this experimental system, the compounds of this application showed efficacy against 5-HT. 2A The receptor exhibits affinity.

[0792] Example 6 evaluates the effect of the compound on 5-HT by beta-arrestin 2 recruitment. 2A Receptor agonism

[0793] Experimental Objective

[0794] The main objective of this experiment was to demonstrate the activity of the compound in the 5-HT2A receptor / beta-arrestin 2 recruitment pathway.

[0795] The experimental reagents and consumables are shown in Table 16:

[0796] Table 16

[0797] The experimental instruments are shown in Table 17:

[0798] Table 17

[0799] Experimental procedure:

[0800] 5-HT2A / ARRB2 OE HEK293T cells were cultured in culture medium. Cells were digested with trypsin, and the digestion was stopped by adding an appropriate amount of culture medium. Cells were centrifuged at 1000 rpm for 5 minutes at room temperature. After discarding the supernatant, the cells were resuspended in Opti-MEM, and 1 mL was used for cell counting. Cell counts and viability were determined using a cell counter. Cells were diluted to 0.75 × 10⁶ / mL, and 40 μL / well of cell suspension was added to 384-well cell culture plates. Cells were incubated overnight at 37°C with 5% CO₂.

[0801] The compound was serially diluted 3-fold at 10 spots using Echo, and 200 nL of the compound was transferred to a compound plate in duplicate. 20 μL of Opti-MEM was added to each well to prepare a 10-fold concentration of the agonist working solution.

[0802] Add 5 μL of luminescent substrate (Furimazine) and 5 μL of the compound to each well in the cell plate. Incubate at 37°C and 5% CO2 for 30–40 minutes, and read the chemiluminescent signal using Envision.

[0803] Data Analysis:

[0804] XL-FIT calculates the EC50 of each test sample on each plate using a four-parameter fitting model.

[0805] Effect (% activity) = 100 × (original signal value - average signal value of low signal control well) / (average signal value of high signal control well - average signal value of low signal control well).

[0806] The signal ratio of the reference standard or sample = the average of the raw data at the maximum dose / the average of the raw data at the minimum dose.

[0807] The experimental results are shown in Table 18:

[0808] Table 18

[0809] Experimental conclusion:

[0810] The test sample was prepared according to the corresponding examples, and the results are shown in the table above. In this test system, the compound of this application showed good performance against 5-HT. 2A The receptor exhibits agonistic activity.

[0811] Example 7: Detection of the effect of the compound on dendrites of primary cortical neurons in rats

[0812] Experimental objective:

[0813] The effects of the compounds on dendrite formation (dendritic growth and branching) in primary rat cortical neurons were evaluated using high-content imaging and Shore analysis.

[0814] The experimental materials are shown in Table 19:

[0815] Table 19

[0816] The experimental instruments are shown in Table 20:

[0817] Table 20

[0818] Experimental procedure:

[0819] Primary neuron separation

[0820] Anatomical sampling:

[0821] Pregnant SD rats at 18 days of age were euthanized, and their brains were rapidly removed using pre-cooled dissection fluid (DMEM + 10% fetal bovine serum + 1% penicillin-dextrose antibody). The cortex was separated and cut into 1 mm³ tissue blocks.

[0822] Enzyme digestion:

[0823] Digestion was performed using collagenase A (2 mg / mL) + DNase I (100 μg / mL) at 37°C for 45 minutes. Digestion was terminated with TrypLE™ Express, and the mixture was washed and resuspended in Neurobasal complete medium.

[0824] Culture plate preparation

[0825] 96-well plates were coated with poly-L-lysine (100 μg / mL) and laminin (10 μg / mL), incubated for 4 hours, and then overnight. After UV sterilization, the plates were seeded at a density of 7,500 cells / well.

[0826] Compound treatment

[0827] Day 5 of culture (DIV5): Add blank control and test compound (1 μM), 3 replicates per group. Day 12 of culture (DIV12): Fix cells and perform MAP2 / DAPI immunofluorescence staining.

[0828] Imaging and Analysis

[0829] Using a 20x objective lens in CellVoyager TM The CQ1 system acquires images.

[0830] ImageJ Plugin Analysis: Simple Neurite Tracer: Tracks dendritic morphology.

[0831] Sholl analysis: Calculate the area under the curve (AUC) at the intersection points in the radius range of 5 to 40 μm.

[0832] The experimental results are shown in Table 21.

[0833] Table 21

[0834] In the Sholl analysis, the area under the curve (AUC) of the intersection points of neuronal dendrites with radii ranging from 5 μm to 40 μm was calculated. Data were processed using Graphpad Prism 8.3 and Excel. One-way ANOVA analysis was performed to analyze statistical differences between groups. Significance was defined as p < 0.05, p < 0.01, and p < 0.001 as highly significant compared to the control group. * represents p < 0.05, ** represents p < 0.01, and *** represents p < 0.001.

[0835] Experimental conclusion: The test sample was prepared according to the corresponding example. The results showed that the area under the curve of the intersection point within the radius range was increased compared with the blank control group. The test sample can promote the growth of primary rat cortical neurons and has the ability to regulate the dendritic plasticity of neurons.

[0836] Example 8: Study on the metabolic stability of the compound in liver microsomes of mice, rats, dogs, monkeys and humans.

[0837] Experimental steps

[0838] 1. Incubation steps

[0839] Test compounds or positive controls (including testosterone, diclofenac, and propafenone) were incubated once at 1.0 μM (solvent: acetonitrile) with liver microsomes (from Corning, Xenotech, or other trusted suppliers, with microsomes from multiple donors for each species) at a final concentration of 0.5 mg / mL (100 mM potassium phosphate buffer (PB Buffer)).

[0840] The mixture will be preheated at 37°C for 10 minutes, and the reaction will be initiated by adding a cofactor system (1.0 mM NADPH). Test compounds incubated with liver microsomes at 37°C without the cofactor system will serve as negative controls.

[0841] 2. Sampling

[0842] Reaction samples will be taken at multiple time points (e.g., 0, 5, 15, 30, 45, and 60 minutes), while samples without the cofactor system (NCF) will be taken at 60 minutes. All samples will be immediately mixed with pre-cooled acetonitrile containing the internal standard (IS) to terminate the reaction.

[0843] 3. Single-point testing

[0844] Each test condition is measured once (n=1).

[0845] 4. Sample Analysis

[0846] The samples will be analyzed using LC-MS / MS; the disappearance of the test compound will be assessed based on the peak area ratio of the analyte to the internal standard (IS) (no standard curve required).

[0847] 5. Data Summary

[0848] Provides an Excel summary of data, including calculated intrinsic clearance rate and half-life (T). 1 / 2 )value.

[0849] 6. Calculation of microparticle clearance rate

[0850] Calculate the microsomal clearance rate using the following formula:

[0851] when

[0852] C t: This indicates the drug concentration at time t;

[0853] C0: represents the drug concentration at the initial time (t=0);

[0854] e: is the base of the natural logarithm, approximately equal to 2.71828;

[0855] k e : Represents the elimination rate constant, describing the rate at which a drug is eliminated from the body;

[0856] t: Indicates time.

[0857] Liver weight: 40 g / kg (rat), 30 g / kg (monkey), 32 g / kg (dog), 20 g / kg (human) and 88 g / kg (mouse).

[0858] Using CL int(mic) Calculate liver clearance rate:

[0859] Microsomal protein / liver weight: 45 mg / g (applicable to 5 species).

[0860] The experimental results are shown in Table 22:

[0861] Table 22

[0862] Experimental conclusion:

[0863] The results showed that the compound of this application has a low liver microsomal clearance rate and good metabolic stability.

[0864] Example 9: Evaluation of the compound's inhibitory activity on hERG potassium ion channels

[0865] Experimental objective:

[0866] The inhibitory effect of the present invention on the hERG (human ether-à-go-go related gene) potassium ion channel was detected using whole-cell manual patch-clamp assay.

[0867] Experimental steps:

[0868] Cell culture and processing:

[0869] CHO cells stably expressing hERG were cultured in 35 mm diameter cell culture dishes at 37°C in a 5% CO2 incubator. They were passaged every 48 hours at a 1:5 ratio. The culture medium consisted of 90% F12 (Invitrogen), 10% fetal bovine serum (Gibco), 100 μg / mL G418 (Invitrogen), and 100 μg / mL Hygromycin B (Invitrogen). On the day of the experiment, the cell culture medium was aspirated, the cells were washed once with extracellular fluid, and then 0.25% Trypsin-EDTA (Invitrogen) solution was added for digestion at room temperature for 3-5 minutes. The digestion solution was aspirated, the cells were resuspended in extracellular fluid, and then transferred to experimental dishes for electrophysiological recording.

[0870] Compound preparation:

[0871] On the day of the test, the compound was prepared into a 20mM stock solution with DMSO, then serially diluted 3 times with DMSO to an intermediate concentration, and finally diluted 500 times with extracellular fluid to obtain the final concentration to be tested.

[0872] Preparation of positive control compound cisapride: Take 10 μL of 150 μM cisapride DMSO stock solution and add it to 4990 μL of extracellular fluid. Dilute 500 times to obtain the final concentration of 300 nM to be tested.

[0873] The final test concentration of DMSO did not exceed 1%, and this concentration of DMSO had no effect on the hERG potassium channel.

[0874] Electrophysiological recording process:

[0875] CHO cells stably expressing the hERG potassium channel were used to record hERG potassium channel currents at room temperature using whole-cell voltage-clamp technique. Glass microelectrodes were fabricated from glass electrode blanks (BF150-86-10, Sutter) using a stretching device. The tip resistance after perfusion with electrode fluid was approximately 2-5 MΩ. The glass microelectrodes were inserted into the amplifier probe to connect to the patch-clamp amplifier. Clamping voltage and data recording were controlled and recorded by computer using pClamp software, with a sampling frequency of 10 kHz and a filtering frequency of 2 kHz. After obtaining whole-cell recordings, the cells were clamped at -100 mV. The step voltage to induce hERG potassium current (IhERG) was applied from -100 mV with a 2-second depolarization voltage to +20 mV, then repolarized to -50 mV, held for 1 second, and then returned to -100 mV. This voltage stimulation was applied every 5 seconds. After confirming that the hERG potassium current was stable (1 minute), the drug delivery process began. For each test concentration of the compound, administer for at least 1 minute to reach steady state or for a maximum of 3 minutes, and test at least 2 cells for each concentration (n≥2).

[0876] Data processing:

[0877] Data analysis and processing were performed using pClamp, GraphPad Prism 8, and Excel software. The degree of inhibition of hERG potassium current (the peak hERG tail current induced at -50mV) by different compound concentrations was calculated using the following formula:

[0878] Inhibition%=[1–(I / Io)]×100%

[0879] Where Inhibition% represents the percentage of inhibition of hERG potassium current by the compound, and I and Io represent the amplitude of hERG potassium current before and after drug administration, respectively.

[0880] Compound IC 50 The following equations were fitted and calculated using GraphPad Prism 8 software:

[0881] Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope))

[0882] Where X is the Log value of the detected concentration of the test sample, Y is the inhibition percentage at the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages, respectively.

[0883] The experimental results are shown in Table 23:

[0884] Table 23

[0885] Experimental conclusion:

[0886] The results of the inhibitory effect of the compounds of this invention on the hERG potassium ion channel are shown in the table above. It can be seen that the compounds of this invention have a low risk of inhibiting the hERG potassium ion channel, even reaching levels above 10 μM.

[0887] Example 10: Evaluation of the pharmacokinetic properties of the compound in mice.

[0888] Experimental objective:

[0889] The pharmacokinetic properties of the embodiments of the present invention in CD-1 mice were evaluated.

[0890] The experimental materials are shown in Table 24:

[0891] Table 24

[0892] Experimental procedure:

[0893] The pharmacokinetic characteristics of the compound after intravenous injection and oral gavage were tested in rodents using a standard protocol. In the experiment, the candidate compound was prepared into a clear solution or suspension using a specified solvent and administered to three mice via single intravenous injection and oral gavage, respectively. The solvent for both intravenous injection and oral gavage was a 10% aqueous solution of sulfobutyl-β-cyclodextrin. Whole blood samples were collected within 8 hours into commercially available EDTA2K anticoagulant tubes, centrifuged to obtain the supernatant plasma sample, and proteins were precipitated by adding acetonitrile solution containing an internal standard. After centrifugation, the supernatant was collected, an equal volume of water was added, and after further centrifugation, the supernatant was injected into the plasma. Blood drug concentrations were quantitatively analyzed and pharmacokinetic parameters were calculated using LCMS / MS.

[0894] The administration method is shown in Table 25:

[0895] Table 25

[0896] The experimental results are shown in Table 26:

[0897] Table 26

[0898] Experimental conclusion:

[0899] The test sample was prepared according to the corresponding examples, and the results showed that the examples of the present invention have good pharmacokinetic properties in mice.

[0900] Example 11 Evaluation of the pharmacokinetic properties of the compound in rats

[0901] Experimental objective:

[0902] The pharmacokinetic properties of the compounds obtained in the embodiments of the present invention in SD rats were evaluated.

[0903] The experimental materials are shown in Table 27:

[0904] Table 27

[0905] Experimental procedure:

[0906] The pharmacokinetic characteristics of the compound after intravenous and oral administration were tested in rodents using a standard protocol. In the experiment, the candidate compound was prepared into a clear solution or suspension using a specified solvent and administered to three rats via single intravenous injection and oral administration, respectively. The solvent for both intravenous and oral administration was a 10% aqueous solution of sulfobutyl-β-cyclodextrin. Whole blood samples were collected within 24 hours into commercially available EDTA2K anticoagulant tubes, centrifuged to obtain the supernatant plasma sample, and proteins were precipitated by adding acetonitrile solution containing an internal standard. After centrifugation, the supernatant was collected, an equal volume of water was added, and after further centrifugation, the supernatant was injected into the plasma. Blood drug concentrations were quantitatively analyzed and pharmacokinetic parameters were calculated using LCMS / MS.

[0907] The administration method is shown in Table 28:

[0908] Table 28

[0909] The experimental results are shown in Table 29:

[0910] Table 29

[0911] *: Oral gavage dosage: 10.0 mg / kg

[0912] Experimental results:

[0913] The test sample was prepared according to the corresponding examples, and the results showed that the compound of this application has good pharmacokinetic properties in rats.

[0914] Activity test: Evaluation of the pharmacokinetic properties of compound 12 in dogs

[0915] Experimental objective:

[0916] The pharmacokinetic properties of the compounds of the present invention in beagle dogs were evaluated.

[0917] The experimental materials are shown in Table 30:

[0918] Table 30

[0919] Experimental procedure:

[0920] The pharmacokinetic characteristics of the compound in beagle dogs after intravenous and oral administration were tested using a standard protocol. In the experiment, the candidate compound was prepared into a clear solution or suspension using a specified solvent and administered to two beagle dogs via single intravenous injection and oral administration, respectively. The solvent for intravenous injection was a 10% aqueous solution of sulfobutyl-β-cyclodextrin, and the solvent for oral administration was also a 10% aqueous solution of sulfobutyl-β-cyclodextrin. Whole blood samples were collected within 24 hours into commercially available EDTA2K anticoagulant tubes, centrifuged to obtain the supernatant plasma sample, and proteins were precipitated by adding acetonitrile solution containing an internal standard. After centrifugation, the supernatant was collected, an equal volume of water was added, and after further centrifugation, the supernatant was injected. Blood drug concentrations were quantitatively analyzed and pharmacokinetic parameters were calculated using LCMS / MS.

[0921] The test sample was prepared according to the corresponding examples, and the compounds of this application exhibited good pharmacokinetic properties.

[0922] Example 13: Compound-induced mouse head-shaking response model

[0923] Experimental objective:

[0924] The effects of the compound on the number of head-shaking events in C57BL6 / J mice were evaluated using a mouse head-twitch response (HTR) model to assess the hallucinogenic effects of the compound in this embodiment of the invention.

[0925] The experimental materials are shown in Table 31:

[0926] Table 31

[0927] Experimental procedure:

[0928] After arriving at the animal facility, the animals will acclimatize for 3 days.

[0929] Based on the animal's weight, administer Zoltil 50 (20 mg / kg, intraperitoneal injection) and xylazine hydrochloride (5 mg / kg, intraperitoneal injection). After anesthetizing the animal (no withdrawal response when the paw is lightly pressed), open the upper part of its scalp and implant a magnetic bead (5 mm in diameter, 2 mm in height) under its scalp. HTR testing will be performed 3 to 7 days after the animal recovers from surgery.

[0930] On the day of the test, the animals will be randomly grouped according to their weight using an Excel random grouping table. The grouping results are shown in Table 32 below:

[0931] Table 32

[0932] Experimental test:

[0933] Before the experiment, the animals were placed in the test room for 1 hour to acclimatize. Head-shaking behavior in the selociline group was recorded for 60 minutes immediately after administration using Noldus software, while head-shaking behavior in the solvent or compound groups was recorded for 60 minutes 30 minutes after administration using Noldus software. A peak threshold was set, and the number of head-shaking events in mice was analyzed, with the cumulative number recorded every 10 minutes.

[0934] Data Analysis:

[0935] Data were collected using Excel and analyzed and plotted using GraphPad Prism. One-way ANOVA and / or two-way ANOVA with subsequent multiple comparisons were used to analyze the number of head movements in each group of animals under different drug treatments. A p-value < 0.0001 was considered statistically significant compared to the solvent group. The experimental results are shown in Table 33.

[0936] Table 33

[0937] Experimental conclusion:

[0938] The test sample was prepared according to the corresponding examples, and the results showed that serozepine significantly increased the number of head shakes in mice. The compound of this application does not increase the number of head shakes in mice and is not hallucinogenic.

[0939] Effects Example 14: Effect of Compound on Activity Level in Mice

[0940] Experimental objective:

[0941] This study investigated the effect of a single oral gavage administration of the compound of the present invention on the activity level of C57BL / 6J mice within 24 hours.

[0942] The experimental materials are shown in Table 34:

[0943] Table 34

[0944] Experimental Groups:

[0945] The experimental animals were placed in the animal facility 5 days in advance and randomly grouped into groups of 8 males each, based on similar weight. A randomization sequence was generated before the experiment, and animals were assigned according to this sequence on the day of the experiment. The grouping is shown in Table 35.

[0946] Table 35

[0947] Experimental procedure:

[0948] The solvent control group was administered the solvent reference standard by gavage, while the test sample group was administered different test samples by gavage.

[0949] Animal activity was tested immediately after drug administration, within 24 hours. Mice were placed in a Phenotyper home enclosure and allowed free movement for 24 hours. Videos were recorded using EthovisionXT video analysis software, and the time spent in the central region and total distance traveled were measured and analyzed. The key metric was the time spent in the central region (s).

[0950] After the test, the animal was removed and the Phenotyper furniture box was wiped clean with 75% alcohol.

[0951] Data Analysis:

[0952] The protocol requires that measured and observed data be manually recorded in appropriate tables or collected directly by computer. Statistical analysis was then performed, with measurement data expressed as mean plus standard deviation. All statistical analyses were conducted using SPSS 19.0 or Graphpad Prism 8.0 statistical software. The experimental results are shown in Table 36.

[0953] Table 36

[0954] Experimental conclusion:

[0955] The test sample was prepared according to the corresponding examples. The results showed that the total movement distance of the mice was not significantly different from that of the solvent control group, and it had no effect on the spontaneous activity of the mice.

[0956] Example 15: Evaluation of the antidepressant efficacy of the compound in a mouse forced swimming model

[0957] Experimental objective:

[0958] The antidepressant efficacy of the embodiments of the present invention in the C57BL / 6J mouse forced swimming model was evaluated.

[0959] The experimental materials are shown in Table 37:

[0960] Table 37

[0961] The experimental groups are shown in Table 38:

[0962] Animals were allowed to acclimatize to the experimental environment for 7 days. Animal weights were recorded before the experiment, and animals were randomly grouped. The grouping details are shown in the table below:

[0963] Table 38

[0964] Experimental procedure:

[0965] Add water of the pre-adjusted temperature to a cylindrical swimming tub for mice, with the water level at two-thirds of the tub's height. Place the mice in the tub and let them swim for 10 minutes. Remove the mice, dry them, and return them to their cages. Conduct the formal test the following day.

[0966] The next day, water of the correct temperature was added to the cylindrical swimming tub for the mice; the position of the forced swimming device and the camera was adjusted, and the computer was connected to record the experimental video; 1 hour after administration, the mice were gently removed from the cage, calmed for 1 minute, and when the animals were no longer stressed, they were placed in the water and immediately moved away from the video recording range.

[0967] The software recorded the mice's swimming over a 6-minute period. After the test, the mice were removed, thoroughly dried, and returned to their cages. This process was repeated until all mice had been tested.

[0968] After the experiment, all animals were euthanized.

[0969] Data analysts evaluated the immobility behavior of mice through video, analyzed the duration of immobility from the 2nd to the 6th minute of the testing phase, and recorded the latency period of immobility during this time; the longer the immobility time, the more severe the depression.

[0970] Data Analysis:

[0971] All raw data were entered into Excel and statistically analyzed using GraphPad Prism 9.0. Data are expressed as Mean ± SEM. One-way ANOVA analysis was performed to analyze statistical differences between groups. Compared with the solvent group, a p-value < 0.05 was considered statistically significant, p < 0.01, and p < 0.001 were considered highly statistically significant. * represents p < 0.05, ** represents p < 0.01, and *** represents p < 0.001.

[0972] The experimental results are shown in Table 39:

[0973] Table 39

[0974] Experimental conclusion:

[0975] The test sample was prepared according to the corresponding examples. The results showed that the compound of this application could significantly reduce the immobility time of forced swimming mice and exhibited good antidepressant efficacy in the C57BL / 6J mouse forced swimming model.

[0976] Efficacy Evaluation of Compound 16 in a Mouse Model of Learned Helplessness and Depression

[0977] Experimental objective:

[0978] The efficacy of the embodiments of the present invention in the C57BL / 6J learned helplessness depression model was evaluated.

[0979] The experimental materials are shown in Table 40:

[0980] Table 40

[0981] Experimental procedure:

[0982] 1. Electric shock training model:

[0983] The experimental mice were placed in an electric stimulation shuttle box and received 120 unpredictable and evasive foot shocks once a day for 8 consecutive days (current intensity 0.3 mA, duration of a single shock random 1-3 s, interval between two shocks random 1-15 s, no light or sound stimulation cue signal given before / during each shock).

[0984] 2. Electric shock escape test and grouping:

[0985] Twenty-four hours after the last electric shock training, the experimental mice underwent 30 shuttle escape electric shock tests. Each test began with a 5-second light stimulus, followed by a 10-second foot shock at an intensity of 0.3 mA, with a 30-second interval between each shock. The shock was terminated when the mouse shuttled from the shocked side to the un-shocked side. Successful escape during the shock was defined as voluntary escape under light stimulation, while unsuccessful escape was defined as escape failure. A mouse with more than 15 escape failures in the 30 tests was defined as having LH (Least Hive) behavior. Animals exhibiting confirmed LH behavior were randomly assigned to groups of eight to ensure that the mean number of escape failures was similar across groups and not statistically significant. The grouping is shown in Table 41 below.

[0986] Table 41

[0987] 3. Drug administration test:

[0988] Twenty-four hours after group selection, the mice were administered drugs according to the group dosing information, and shuttle-escape electric shock tests were conducted at 1 hour and 24 hours after drug administration (using the same method as above). After the experiment, the experimental apparatus was properly stored and the mice were euthanized.

[0989] Data Analysis:

[0990] All data analyses were performed using GraphPad Prism 10.0 software for statistical analysis and graphing. Results are expressed as mean ± standard error (Mean ± SEM). Post-drug administration data were analyzed using two-way ANOVA, and Fisher's LSD method was used for inter-group comparisons. For comparisons with the solvent group, p < 0.05 was considered statistically significant, p < 0.01, and p < 0.001 were considered highly statistically significant. * represents p < 0.05, ** represents p < 0.01, and *** represents p < 0.001.

[0991] The experimental results are shown in Table 42.

[0992] Table 42

[0993] Experimental conclusions: The test sample was prepared according to the corresponding examples. The results showed that the compound of this application could significantly reduce the number of escape failures in animals in the learned helplessness experiment and alleviate depressive-like behavior after administration for 1 h and 24 h, and showed good antidepressant efficacy in the C57BL / 6J learned helplessness depression model.

[0994] Efficacy Evaluation of Compound 17 in a Mouse Model of Chronic Unpredictable Mild Stress Depression

[0995] Experimental objective:

[0996] A mouse model of chronic unpredictable mild stress (CUMS) was constructed, and the efficacy of the drug in the depression model of the present invention was evaluated by the sucrose preference test (SPT) and the forced swimming test (FST).

[0997] The experimental materials are shown in Table 43:

[0998] Table 43

[0999] Experimental procedure:

[1000] 1. Adaptation

[1001] The animals were allowed to adapt to the environment for 7 days. During this period, the animals were subjected to 1-2 minutes of acclimatization touch and handling for 5 consecutive days.

[1002] 2. Baseline test of sugar water preference

[1003] Before the experiment, mice were housed individually in the laboratory for 24 hours to acclimatize. On the first day, they were given two bottles of plain water for acclimatization; on the second day, they were given two bottles of 1% glucose solution. a,b For acclimatization, on the third day, acclimatize with one bottle of 1% sugar solution and one bottle of regular water. On the fourth day at 5:00 PM, weigh the sugar solution and record the initial weight of the water bottle. On the fifth day at 9:30 AM, weigh the sugar solution again and record the weight of the water bottle after consumption. If the preference level is not high (the average sugar solution preference index of each group should be 0.85 or higher), continue testing sugar solution preference at 5:00 PM on the fifth day and 9:30 AM on the sixth day. After each weighing, swap the positions of the sugar solution and regular water to prevent the formation of positional preference.

[1004] Note: a. Sucrose Preference Index = Sugar water intake / (Sucrose water intake + Ordinary drinking water intake). b. 1% sugar water: 0.01g / mL sucrose aqueous solution.

[1005] 3. Grouping

[1006] Based on the baseline test results of sucrose preference, the test animals were randomly divided into a normal solvent group, a model group, a positive control drug group, and a compound group of the examples.

[1007] 4. Modeling

[1008] Based on the baseline sucrose preference test results before modeling, animals were randomly assigned to groups. Except for the normal solvent control group, the other groups were randomly given a mild stressor daily for four consecutive weeks. After each week's stress training, the animals underwent a sucrose preference test and were weighed. When the sucrose preference index was ≤0.70, the mice were considered to have developed anhedonia-like depressive behavior, and the CUMS model was considered successful. Based on the sucrose preference test results and mouse weight results in the fourth week, the other groups (excluding the normal solvent control group) were regrouped, with 12 mice in each group, as shown in Table 44 below.

[1009] Table 44

[1010] 5. Drug administration test

[1011] One hour after administration on the first day, the FST test was performed, followed by the SPT test. The administration was continued for seven days. On the seventh day, behavioral tests were performed one hour after administration, following the same order as on the first day. During this period, animals were continuously given mild stress randomly.

[1012] Data Analysis:

[1013] Data were collected using Excel software. Prism 10.1.2 (Graph pad software, Inc.) software was used for data analysis and graphing; bar charts were created for data on sucrose preference and forced swimming. One-way ANOVA and LSD multiple comparison tests were used to compare data between animal groups. A p-value < 0.05 was considered statistically significant compared to the model group; p < 0.01, p < 0.001, and p < 0.0001 were considered highly statistically significant. * represents p < 0.05, ** represents p < 0.01, *** represents p < 0.001, and **** represents p < 0.0001.

[1014] The experimental results are shown in Table 45.

[1015] Table 45

[1016] Experimental conclusions: The test sample was prepared according to the corresponding examples. The results showed that, compared with the model group, single or continuous oral gavage administration of the compound of this application significantly improved the depressive-like behaviors such as despair and anhedonia in the model mice (the sucrose preference test was used to evaluate the degree of anhedonia in the animals, and the forced swimming test was used to evaluate the degree of despair in the animals), and showed good antidepressant efficacy in the mouse CUMS model.

[1017] While specific embodiments of the present invention have been described above, those skilled in the art should understand that these are merely illustrative examples, and various changes or modifications can be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims.

Claims

A compound as shown in formula (II), a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof: wherein, the configuration of the carbon atom marked "*" is R configuration, S configuration or a mixture thereof; R is C1-C6alkyl, C3-C6cycloalkyl, C2-C6alkynyl or substituted C1-C6alkyl; a substituted C1-C6alkyl; R a D, OH, C3-C6cycloalkyl, cyano, halogen or -S(=0)2Ci-C6alkyl; X1is N or CH; X2is N or CR 2 ; R 2 R is H or halogen; R 1 is H, hydroxyl, halogen, CN, C1-C6 alkyl, -S(=0)2C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C1-C6 alkyl substituted by one or more R 1-1 substituted C1-C6 alkyl or C1-C6 alkoxy substituted by one or more R 1-2 substituted C1-C6 alkyl or C1-C6 alkoxy substituted by one or more R R 1-1 and R 1-2 each independently is halogen; or R 1 with the atom to which they are attached form a 5-6 membered heterocycloalkenyl, wherein the heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; 2 with the atom to which they are attached form a 5-6 membered heterocycloalkenyl, wherein the heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; X3is N or CR 3 ; R 3 R is H or halogen; or R 3 with the atom to which they are attached form a 5-6 membered heterocycloalkenyl, wherein the heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; 1 with the atom to which they are attached form a 5-6 membered heterocycloalkenyl, wherein the heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; X4is N or CR 4 ; R 4 R is H or halogen; R 5 R is H or C1-C6 alkyl; The compound of Formula (I) is not any one of the following: the compound represented by formula (II) according to claim 1, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, R 1 is H, halogen, CN, C1-C6-alkyl, -S(=O)2C1-C6-alkyl, C1-C6-alkoxy, C3-C6-cycloalkyl, C1-C6-alkyl substituted by one or more R 1-1 substituted C1-C6-alkyl or one or more R 1-2 substituted C1-C6-alkyl or one or more R The compound, the pharmaceutically acceptable salt thereof, the solvate thereof, or the solvate of the pharmaceutically acceptable salt thereof according to Claim 1, wherein The compound is a compound as shown in formula (I): wherein, For preferably For R is C1-C6alkyl, C3-C6cycloalkyl, C2-C6alkynyl or substituted by one or more R a substituted C1-C6alkyl; R a is D, OH, C3-C6cycloalkyl, cyano, halogen or -S(=0)2Ci-C6alkyl; X1is N or CH; X2is N or CR 2 ; R 2 is H or halogen; R 1 is H, halogen, CN, C1-C6-alkyl, -S(=O)2C1-C6-alkyl, C1-C6-alkoxy, C3-C6-cycloalkyl, C1-C6-alkyl substituted by one or more R 1-1 substituents, C3-C6-cycloalkyl substituted by one or more R 1-2 substituents, C1-C6-alkoxy substituted by one or more R R 1-1 and R 1-2 each independently halogen; or R 1 with the atom to which they are attached form a 5-6 membered heterocycloalkenyl, wherein the heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; 2 with the atom to which they are attached form a 5-6 membered heterocycloalkenyl, wherein the heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; X3is N or CR 3 ; R 3 R is H or halogen; or R 3 with the atom to which they are attached form a 5-6 membered heterocycloalkenyl, wherein the heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; 1 with the atom to which they are attached form a 5-6 membered heterocycloalkenyl, wherein the heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; X4is N or CR 4 ; R 4 is H or halogen; The compound of Formula (I) is not any one of the following: The compound, the pharmaceutically acceptable salt thereof, the solvate thereof, or the solvate of the pharmaceutically acceptable salt thereof according to at least one of claims 1 to 3, characterized in that The compound is also not any of the following: The compound, the pharmaceutically acceptable salt thereof, the solvate thereof, or the solvate of the pharmaceutically acceptable salt thereof according to at least one of claims 1 to 4, characterized in that one or more of the following conditions are satisfied: (1) each "halogen" is independently F, CI, Br or I, for example F; (2) each "C1-C6alkoxy" is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, for example methoxy, ethoxy or isopropoxy; (3) each "C1-C6alkyl" is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl, ethyl, isopropyl or isobutyl; (4) each "C2-C6alkynyl" is independently ethynyl, propynyl or propargyl, for example ethynyl; (5) each "C3-C6cycloalkyl" is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl; (6) each "5-6 membered heterocycloalkenyl" is independently a 5-6 membered heterocycloalkenyl having 1 or 2 heteroatoms which are O, for example a dihydrofuran or dihydropyran ring, further for example The compound, the pharmaceutically acceptable salt thereof, the solvate thereof or the solvate of the pharmaceutically acceptable salt thereof according to at least one of claims 1 to 4, characterized in that one or more of the following conditions are satisfied: (1) For (2) R is -CH3, -CD3, -CH2CH3, (3) R 5 is -H or -CH3; (4) R 1 is Ci-C6alkoxy or halogen. The compound, the pharmaceutically acceptable salt thereof, the solvate thereof, or the solvate of the pharmaceutically acceptable salt thereof according to at least one of claims 1 to 4, characterized in that one or more of the following conditions are satisfied: (1) For (2) R is -CH3or (3) R 1 is methoxy or F. The compound, the pharmaceutically acceptable salt thereof, the solvate thereof or the solvate of the pharmaceutically acceptable salt thereof according to at least one of claims 1 to 4, characterized in that one or more of the following conditions are satisfied: (1) R is -CH3, -CD3, -CH2CH3, for example -CH3; (2) R 2 is H or F, or, R 1 and R 2 together with the atom to which they are attached form a (3) R 1 -H, -F, -CN, -CH3, -CF3, -OCH3, preferably -H, -F, -CN, -CF3, -OCH3, or R 1 and R 2 with the atom to which they are attached, form a (4) R 3 is H or F; (5) R 4 is H or F. The compound, the pharmaceutically acceptable salt thereof, the solvate thereof or the solvate of the pharmaceutically acceptable salt thereof according to at least one of claims 1 to 4, characterized in that one or more of the following conditions are satisfied: (1) R is C1-C6alkyl; (2) R 2 is H; (3) R 1 C1-C6alkoxy, for example methoxy; (4) R 3 is H; (5) R 4 is H. The compound, the pharmaceutically acceptable salt thereof, the solvate thereof, or the solvate of the pharmaceutically acceptable salt thereof according to at least one of claims 1 to 9, characterized in that any one of the following conditions is satisfied: (1) For (2) For (3) For (4) For (5) X2is CR 2 , R 1 and R 2 together with the atoms to which they are attached form a 5-6 membered heterocyclene, for example The compound, the pharmaceutically acceptable salt thereof, the solvate thereof or the solvate of the pharmaceutically acceptable salt thereof according to at least one of claims 1 to 9, characterized in that For The compound, the pharmaceutically acceptable salt thereof, the solvate thereof, or the solvate of the pharmaceutically acceptable salt thereof according to at least one of claims 1 to 4, characterized in that the compound is any one of the following: Case 1: For R is C1-C6alkyl or C1-C6alkyl substituted with one or more hydroxyl groups, for example C1-C6alkyl; R 1 halogen or Ci-C6alkoxy; R 2 , R 3 , and R 4 are each independently H or halo; Case 2: For R 1 is halogen or Ci-C6alkoxy; R is C1-C6alkyl; Case 3: For R 1 With R 2 The atoms connected to them together form a 5-6 membered heterocyclic alkene, wherein the heteroatom is O and the number of heteroatoms is 1; R is C1-C6alkyl or C1-C6alkyl substituted with one or more hydroxyl groups; Case 4: For R 1 is Ci-C6-alkoxy; R is C1-C6alkyl. The compound, the pharmaceutically acceptable salt thereof, the solvate thereof, or the solvate of the pharmaceutically acceptable salt thereof according to Claim 1, wherein The compound is any one of the following compounds: A pharmaceutical composition comprising a compound according to at least one of claims 1 to 13, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant. The use of a compound according to at least one of claims 1 to 13, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 14, said use being selected from one or more of the following: (1) the use in the manufacture of a medicament for modulating neuronal plasticity; (2) the use in the manufacture of a medicament for the prevention and / or treatment of depression, schizophrenia, anxiety or post-traumatic stress disorder; (3) in the manufacture of a 5-HT 2A receptor agonist; preferably, the 5-HT 2A receptor agonist is a 5-HT 2A selective receptor agonist, for example a 5-HT 2B selective receptor agonist with respect to 5-HT 2A ; (4) use in the manufacture of a medicament for the prevention and / or treatment of a disease associated with 5-HT 2A receptors; preferably, the disease associated with 5-HT 2A receptors is depression, schizophrenia, anxiety or post-traumatic stress disorder.

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